Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/084739
PCT/IB2021/000708
COMPOUNDS AND METHODS FOR THE TREATMENT OF OCULAR DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
100011 This application claims the benefit of U.S. Provisional Application No.
63/094,808, filed
October 21, 2020, the content of which is incorporated by reference herein in
its entirety.
BACKGROUND OF THE DISCLOSURE
100021 Restasis (0.05% cyclosporine A, Allergan) was approved by the Food and
Drug
Administration (FDA) to increase tear production in patients whose tear
production is presumed
to be suppressed due to ocular inflammation associated with
keratoconjunctivitis sicca. Xiidra
(lifitegrast ophthalmic solution) 5% is indicated for the treatment of signs
and symptoms of dry
eye disease (DED).
SUMMARY OF THE DISCLOSURE
100031 Provided in certain embodiments herein are compounds, pharmaceutical
(e.g., ophthalmic)
compositions, and methods of treatment In specific embodiments, methods of
treatment provided
herein include the treatment of ocular and/or periocular indications or
abnormalities. In some
embodiments, the ocular and/or periocular indications or abnormalities treated
by or with a
composition or compound provided herein are indications or abnormalities that
have
multifactorial etiologies and/or interactions. In certain embodiments provided
herein are
compounds (and compositions comprising such compounds) that have
multifunctional efficacies,
such as when administered in or around the eye (e.g., to the ocular surface,
the eyelid, such as the
eyelid margin or the inner surface of the eyelid, or the like).
100041 In some embodiments, provided herein is a method of treating
inflammation or
hyperkeratosis (e.g., of the eye or skin).
100051 In certain embodiments, methods provided herein involve the method of
treating
meibomian gland dysfunction (MGD).
100061 Currently there are no approved pharmacological agents useful for the
treatment of MGD.
The recognition that terminal duct obstruction from hyperkeratinization of the
ductal epithelium
on meibomian glands is a core mechanism behind meibomian gland dysfunction
(MGD) is
consistent with clinical experience demonstrating that effective treatments
for MGD require
resolution of ductal obstruction and evacuation of glandular contents (Nichols
et al, 201 1 ; Lane et
al, 2012; Blackie et al, 2015). Warm compresses and thermal/mechanical devises
(e.g., LipiFlow)
are used in an attempt to raise the internal temperature of the meibomian
glands over the normal
-1-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
melting point for meibum (i.e., 32 C to 40 C) in an attempt to resolve
terminal duct obstruction
(Lane et al, 2012). Unfortunately, warm compresses are unable to achieve this
benefit for severely
obstructed glands which can having a melting point > 40 C. Current technology
for removing
keratinized obstruction of the meibomian gland also includes physical removal
methods (e.g.,
debridement and gland probing), which are quite painful to patients.
100071 Subsequent to a period of MGD, various stages of inflammatory or
bacterial disease at the
ocular surface are frequently observed because meibomian gland obstruction can
cause a cascade
of events that include further deterioration of the glands (Knop, IOVS, 2011)
from stasis of the
meibum in the secretory glands, mechanical pressure and stress from glandular
obstruction, and
increased bacterial growth that is associated with the downstream release of
bacterial lipases, toxic
mediators, and/or inflammatory mediators. All these factors reduce the quality
and/or quantity of
meibum the glands can release which in turn can cause chronic mechanical
traumatization of the
conjunctival, corneal and eyelid tissues which will lead to further tissue
damage and the release
of inflammatory mediators. Thus, many patients suffering from MGD also have
inflammatory
disease affecting their conjunctiva, cornea, larcrimal gland, lids or goblet
cells causing comorbid
conditions such as dry eye syndrome or blepharitis for which there is an unmet
medical need.
100081 For example, literature has used the terms posterior blepharitis and
MGD as if they were
synonymous, but these terms are not interchangeable. Posterior blepharitis
describes inflammatory
conditions of the posterior lid margin, of which MGD can be one possible
cause. In its earliest
stages, MGD may not be associated with clinical signs characteristic of
posterior blepharitis. At
this stage, affected individuals may be symptomatic, but alternatively, they
may be asymptomatic
and the condition regarded as subclinical. As MGD progresses, symptoms develop
and lid margin
signs, such as changes in meibum expressibility and quality and lid margin
redness, may become
more visible. At this point, an MGD-related posterior blepharitis is said to
be present.
100091 In certain embodiments, provided herein are methods of treating ocular
(or dermatological)
disorders associated with keratosis (e.g., lid keratosis, surface ocular
keratosis, and/or gland
blockage ¨ such as in MGD), microbial infiltration/infection (e.g., bacterial
infiltration/infection),
and/or inflammation (such as inflammation associated keratosis or not
associated with keratosis).
In certain instances, disorders of the skin and/or eye (and/or surround
tissue/skin) are difficult to
differentially diagnose and/or have multiple etiologies. For example, in some
instances, it can be
difficult to distinguish between ocular disorders that involve (1)
inflammation only, (2)
inflammation associated with keratolytic activity, (3) inflammation associated
with both
keratolytic activity (e.g., inducing keratosis) and microbial infiltration,
(4) keratolytic activity, but
-2-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
not inflammation and/or microbial infiltration, or various other combinations.
In some instances,
compounds and compositions provided herein can be used in such ocular and/or
dermatological
indications without the need for differential diagnosis (which can be
difficult, e.g., because of
similar symptom scores, etc.). Further, many ocular and/or dermatological
disorders involve
multiple etiologies, such inflammation, microbial infiltration, keratolytic
activity, or various
combinations thereof. As a result, therapeutic agents, such as those described
herein, that target
multiple etiologies are beneficial in providing therapeutic efficacy, such as
by targeting both an
underlying condition (e g , keratolytic activity and/or microbial
infiltration) and a symptom, such
as inflammation or dry eye.
100101 As such, provided herein are compounds, compositions, methods, and
formulations for the
treatment of ocular (e.g., peri ocular) or dermatological disorders, such as
those having
abnormalities having multifactorial etiologies. In specific embodiments,
ocular disorders include,
by way of non-limiting example, surface disorders, such as MGD, dry eye and
associated
inflammatory and bacterial disease.
100111 Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (I):
R12 0 R2
(R13,
0 R1
R4
R3 0
Formula (I)
100121 In some embodiments, le is aryl, cycloalkyl, heterocyclyl, or
heteroaryl, wherein the aryl,
cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted. In some
embodiments, le, le, and
R4 are each independently H, cyano, halo, ester, alkoxy, alkyl, heteroalkyl,
cycloalkyl or
heterocyclyl, wherein the alkoxy, alkyl, heteroalkyl, cycloalkyl or
heterocyclyl is optionally
substituted. In some embodiments, le' is -La-R12a, wherein La is a bond,
alkyl, or heteroalkyl, and
R12a is absent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,
wherein the cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is optionally substituted. In some
embodiments, In some
embodiments, each RH is independently H, cyano, halo, alkoxy, alkyl,
heteroalkyl, cycloalkyl or
haloalkyl. In some embodiments, n is 0-6. In some embodiments, RQ is - L'-D.
In some
embodiments, D is a keratolytic agent. In some embodiments, L' is a linker.
-3-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100131 In some embodiments, L' comprises one or more linker groups, each
linker group being
selected from the group consisting of a bond, -0-, -S-, halo, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), disulfide, ester, and carbonyl (>C=0). In some embodiments,
L' comprises one
or more linker groups, each linker group being selected from the group
consisting of a bond, -0-,
-S-, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide, ester, and
carbonyl (>C=0). In
some embodiments, each linker group is selected from the group consisting of a
bond, -0-, -S-,
halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), and ester. In some
embodiments, each linker
group is selected from the group consisting of a bond, -0-, -S-, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), and ester. In some embodiments, each linker group is
selected from alkyl
(alkylene) and heteroalkyl (heteroalkylene), the alkyl (alkylene) or
heteroalkyl (heteroalkylene)
being optionally substituted.
100141 In some embodiments, L' is alkyl (alkylene) substituted with oxo and
one or more of alkyl
and heteroalkyl. In some embodiments, the alkyl or heteroalkyl is substituted
with one or more
halo, alkyl, or haloalkyl. In some embodiments, the alkyl or heteroalkyl is
substituted with one or
more alkyl or haloalkyl. In some embodiments, L' comprises one or more linker
group, each linker
group being independently selected from a bond, -0-, -S-, (C=0), -(C=0)alkyl-,
-
(C=0)heteroalkyl-, -(C=0)0-, -(C=0)0alkyl-, -(C=0)0heteroalkyl-, -(C=0)S-, -
(C=0)Salkyl-, -
(C=0)Sheteroalkyl-, alkylene, or heteroalkylene, where each alkyl,
heteroalkyl, alkylene, or
heteroalkyl is independently optionally substituted. In some embodiments, L'
comprises one or
more linker group, each linker group being independently selected from -0-,
(C=0), -(C=0)alkyl-
, -(C=0)h eteroal kyl -, -(C=0)0-, -(C=0)0alkyl -(C=0)0heteroalkyl -
(C=0)0alkyl 0-, -
(C=0)0heteroalky10-, -(C=0)S-, -(C=0)S alkyl-, -(C=0)Sheteroalkyl-, alkylene,
and
heteroalkylene. In some embodiments, L' comprises -0-, -(C=0)alkyl-,-(C=0)0-, -
(C=0)0alkyl-
, and/or-(C=0)0alky10-.
100151 In some embodiments, the linker comprises the structure of Formula (A):
V\G2):Y
Formula (A)
wherein:
Q is a bond, -0-, -S-, or optionally substituted amino;
G-1 and G2 are each independently hydrogen, halo, alkyl, heteroalkyl, or
cycloalkyl,
wherein the alkyl or cycloalkyl is optionally substituted; and
-4-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
g is 1-20.
[0016] In some embodiments, the compound comprises more than one linker of
Formula (A). In
some embodiments, Q is a bond or -0-. In some embodiments, Q is -0- and each
GI and G2 is
independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl
are optionally
substituted. In some embodiments, Q is a bond or -0- and each GI- is hydrogen
and each G2 is
independently alkyl or haloalkyl. In some embodiments, Q is a bond or -0- and
each GI- is
hydrogen and each G2 is methyl. In some embodiments, Q is a bond or -0- and
each GI- and G2 is
hydrogen. In some embodiments, Q is -0-, each GI is hydrogen, and each G2 is
methyl. In some
embodiments, Q is -0- and each GI and G2 is hydrogen.
[0017] In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some
embodiments,
g is 1-5. In some embodiments, g is 2. In some embodiments, g is 1.
100181 In some embodiments, g is 1 or 2, Q is a bond and each GI is hydrogen,
and each G2 is
methyl. In some embodiments, g is 1 or 2, Q is a bond, and each GI and G2 is
hydrogen. In some
embodiments, g is 1 or 2, Q is -0-, each GI is hydrogen, and each G2 is
methyl. In some
embodiments, g is 1 or 2, Q is -0-, and each GI- and G2 is hydrogen.
[0019] In some embodiments, the linker comprises one or more bond, -0-,
methylene,
sky0,s,
g , or
[0020] In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some
embodiments,
g is 1-8. In some embodiments, g is 1, 2, 3, 4, 5, 6, 7, or S.
[0021] In some embodiments, the linker comprises one or more of:
-s? and/or
100221 In some embodiments, the linker comprises a bond, methylene,
.k22,
, or
[0023] In some embodiments, the linker comprises:
=
100241 In some embodiments, the linker is:
Alro,roõis
or 0
-5-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100251 In some embodiments, any linker or L provided herein is attached to the
rest of a molecule
provided herein to form a ketal. In some embodiments, any linker or L provided
herein is attached
to the rest of a molecule provided herein to form an ester.
100261 In some embodiments, the linker is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C-0)0CH2CH2CH2-.
100271 In some embodiments, D comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
100281 In some embodiments, D comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
lipoic acid sulfonyl
(Lipsulf), a radical of N-acetyl cysteine (NAC), a radical of cysteine (Cys),
a radical of glutathione
(GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).
100291 In some embodiments, D comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
100301 In some embodiments, D comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
-6-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100311 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC]-, [Cys-Cys]-, [difiLip-NAC-NAC]., [diHLip-NAC]=, [difiLip-Cap-Cap].,
[diHLip-Cap]=,
[diElLip-Cys-Cys]-, [diElLip-Cys]-, [diElLip-Lipox-Lipoxi-, and [difiLip-
Lipox]...
100321 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, substituted (e.g.,
straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (N-)
substituted with alkyl
(e g , further substituted with oxo and/or thiol)) In some embodiments, the
substituted alkyl is
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
independently selected from the group consisting of -OH, -SH, -COOH,
substituted unsaturated
cycloalkyl (e.g., being substituted with one or more C1-C4 alkyl), and
substituted or unsubstituted
(disulfide containing) heterocycloalkyl (e.g., dithiolanyl, dithiolanyl
sulfone, and dithiolanyl
oxide). In some embodiments, the substituted alkyl is substituted with one or
more (alkyl)
substituent, at least one (alkyl) substituent being independently selected
from the group consisting
of -SH, substituted unsaturated cycloalkyl (e.g., being substituted with one
or more C1-C4 alkyl),
and substituted or unsubstituted disulfide containing heterocycloalkyl (e.g.,
dithiolane oxide). In
some embodiments, the substituted alkyl is substituted with one or more
(alkyl) substituent, at
least one (alkyl) substituent being independently selected from the group
consisting of -SH,
substituted unsaturated cycloalkyl (e.g., being substituted with one or more
Ci-C4 alkyl), and
dithiolanyl oxide. In some embodiments, the substituted heteroalkyl is
substituted with one or
more (heteroalkyl) substituent, at least one (h etero al kyl) substituent
being in dependently selected
from the group consisting of dithiolanyl, dithiolanyl sulfone, dithiolanyl
oxide, -SH, -COOH, and
thioalkyl, the substituted alkyl, substituted heteroalkyl, or substituted
heterocycloalkyl being
further optionally substituted. In some embodiments, the substituted
heteroalkyl is substituted
with one or more (heteroalkyl) substituent, at least one (heteroalkyl)
substituent being
independently selected from the group consisting of -SH, -COOH, and thioalkyl,
the substituted
alkyl, substituted heteroalkyl, or substituted heterocycloalkyl being further
optionally substituted.
100331 In some embodiments, the substituted heterocycloalkyl is saturated
(e.g., dithiolanyl,
dithiolanyl sulfone, or dithiolanyl oxide).
100341 In some embodiments, D is alkyl substituted with dithiolanyl. In some
embodiments, L' is
-(C=0)0CH2-, -(C=0)0CH2CH2-, or -(C=0)0CH2CH2CH2.-. In some embodiments, D is
alkyl
substituted with dithiolanyl and L' is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-.
-7-
CA 03196146 2023- 4- 18
WO 2022/084739 PC
T/IB2021/000708
100351 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, substituted (e.g.,
straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (N-)
substituted with alkyl
further substituted with oxo and/or thiol). In some embodiments, the
substituted alkyl is
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
independently selected from the group consisting of -SH and dithiolanyl oxide.
In some
embodiments, the substituted heteroalkyl is substituted with one or more
(heteroalkyl) substituent,
at least one (heteroalkyl) substituent being independently selected from the
group consisting of -
SH, -COOH, and thioalkyl, the substituted alkyl, substituted heteroalkyl, or
substituted
heterocycloalkyl being further optionally substituted.
100361 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxyl, thiol,
amino, acetamide, -
COOH, substituted unsaturated cycloalkyl (e.g., being substituted with one or
more Cl-C4 alkyl),
unsubstituted (saturated) heterocycloalkyl (e.g., dithiolanyl),
and substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl oxide or dithiolanyl sulfone).
100371 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of thiol, amino,
acetamide, substituted
unsaturated cycloalkyl (e.g., being substituted with one or more CI-CI alkyl),
and substituted
(saturated) heterocycloalkyl (e.g., dithiolanyl oxide).
100381 In some embodiments, D comprises:
0
NH
S H N H2
H ..1.r...õõA
HS HS
HO\ HO \/\)a?? 0
`s'
0
08
S S
or ss'
-8-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0039] In some embodiments, D comprises:
0
00
SH NH2 }L NH SIS
HSõ.õ)HS ./
2-
[0040] In some embodiments, D comprises:
HO
[0041] In some embodiments, D comprises:
[0042] In some embodiments, D comprises:
Ha.l.r.õ)\
0
[0043] In some embodiments, D comprises:
.55
sc. .
[0044] In some embodiments, D comprises:
-XI
100451 In some embodiments, D comprises:
NH2
[0046] In some embodiments, D comprises:
0
NH
[0047] In some embodiments, D comprises:
Oe
Sis
[0048] In some embodiments, D comprises:
S¨s
-9-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100491 In some embodiments, D comprises:
p o
s¨s'-_0
C---1....------../\.,
-e- .
100501 In some embodiments, D comprises:
o,ii
o
NS"-S
c...)\....,../ \......./ \.,..5.,
SS' .
100511 In some embodiments, D-L' is:
I si
-0
00
OH L-,_-=OH, 0 0 ,--1, _Y-... OH )-
., I,
0 0"--N"-----
NOH
,
is(0 0 NH2
HS.,),..1.(0 0
HS-Th-r(DI--(Dy HSC)'"-ry
---r- --s,
0 , 0 0 0
,
0
)LNH I.`-o CI 40
S¨S
HS.....1-.1r0T O o s
N, 1.,,....-.., S, 0
/
0 0
,
,
40 0 40 0 e le`o o
0,,o
0 0 0
s s s
, , ,
0
o
s4o o sis
1-... sõc, o,,ro,isse
o s(
--0 ,or o .
-10-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100521 In some embodiments, D-L' is:
0
NH2 -)LNH
HSipy HS HS OTO,isss HS-HT,0 0
-ly0y0 )55 51
0 0 0 0
, or
sIs
()To/
100531 In some embodiments, D is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
further substituted with oxo and thiol).
100541 In some embodiments, D comprises:
Ns
N'ys
HS 0 , 0 , or.
100551 In some embodiments, D comprises:
N
HS
100561 In some embodiments, D comprises:
><SN-Di
0
100571 In some embodiments, D comprises:
N
0
100581 In some embodiments, D comprises:
õss
N z
-3_1-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100591 In some embodiments, D-L' is:
><7
0
---µ 0 I I
HS 0 0 ,
or
0
100601 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
100611 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl comprising
one ester (e.g., within the (e.g., linear or branched) heteroalkyl chain).
100621 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
100631 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one amide (e.g., within the (e.g., linear
or branched)
heteroalkyl chain).
100641 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
100651 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
100661 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and/or one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
100671 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycl oal kyl substituted with carboxyl i c acid).
-12-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
[0068] In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (e.g., N-
attached) heterocycloalkyl (e.g., optionally substituted with carboxylic
acid).
[0069] In some embodiments, D is substituted branched heteroalkyl.
[0070] In some embodiments, D comprises:
0
0 H N
OH HOy,1
HN 0 S,s
0
0
0 OH HO 0 ,
or
OH
0
0
,s
HO 00 S
[0071] In some embodiments, D comprises:
OH
0 0
HN)L"'ON
HOy-L.,1
0 S,
HO 0
0 S,
HO 0 or
-13-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100721 In some embodiments, D comprises:
SH
S¨s 0 0
H
C)'ss HOAT--)N N
õ..,....-\
cs' H
0 NH2 0
0
HN)L''`.
HOyH
o SH --y0 0 S,
S
0 o "SH
H
Iõ,_.---õ õSõ,_.õ1õ,_.----õ,õ---õ/
S N-11\10H H7(IL .--.,"
H N HN
,
NH2 0 H r H 00
,
OH
0
0 0 .-i-D
sOH
H r H N ,r,_
HO 00 ----Th
S,s
0
0
00H
Oy-
0
HS,.,=,.. NH
NH
0 NH2
HOS 0 0 H N _.,...õ---õ. S ,Sõ,....õ-Ly --)1.- NH
)YS
NH2 )/
HO0 HS
,or
ss-
.
-14-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100731 In some embodiments, D comprises:
SH
0 0 0 -'-SHH 0
H
0 .SH
H0)-1-)(NThr N'''-'\2' ssssey-}LNIT-N---j''OH HS*1,N,---,
/
H H
NH2 0 , NH2 0
H ,
OH
0 0
HN)L- 0 .)-Ni D
HO,IrL1
...,r,0 0 S,s ../"-1
0 S,
HO --...rj\I 0 S
HN
)S'S5,5
,--k,
HO 0
Oy-
0
HS,--,...NH
) N H
0 NH2 0
0 0 HN3,Sõ,_,..L,.ccs --A.NH
HO-itS'S5/ >y I HS
NH2 H 0"--0 , or
/ /
100741 In some embodiments, D comprises:
S¨S
Thi0,,sc
0 .
100751 In some embodiments, D comprises:
0
ss557S'S-*LOH
H H N .1(
N y-S 0
0
00H .
100761 In some embodiments, D comprises:
SH
0 0
HO
-jANH-Xli
NH2 0 .
-15-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100771 In some embodiments, D comprises:
SH
0 0
sssssNirF}LOH
NH2 0
100781 In some embodiments, D comprises:
0 rSH
HSNC5,
100791 In some embodiments, D comprises:
0
HN-j
HOy1,1
--y0 S,s
100801 In some embodiments, D comprises:
OH
0
trID
0 ,s
HO 0 S
100811 In some embodiments, D comprises:
0 NH2
H0rS-S-'-11
NH2
100821 In some embodiments, D comprises:
HS
0 0
-16-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
100831 In some embodiments, D comprises:
NH
-
HOO
100841 In some embodiments, D comprises:
0
).L-NH
HSJy
100851 In some embodiments, D-L' is:
0 S-s AO 0 0
0 or
100861 In some embodiments, D-L' is:
gs(0 0 0
OH
0
0
0 OH
100871 In some embodiments, D-L' is:
0 0 0 0 0 0
H
HO'Bry-'11TrirN'"-A010;\
OH NMI
N H2 0 NH2 0
0
HNIA-
H0y-ci
SH --y0 0 5,
0
õ
HS7ci-L,N,,,TrOTO,;" 0/
0
0 HO 0
-17-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
OH
0
ON--D
--/\1
0 S,s
HO 0 0 NH2
0 I NH2 0 1
HS 0 0
-)L
0 0 NH )(NH
HS
0
Toss
01 HO 0 , or 0
100881 In some embodiments, D comprises: HOCH2(C=0)0-, HOCH(CH3)(C=0)0-,
HO(CH2CH20)4CH2(C=0)0-, HO(CH2CH20)4CH2CH2(C=0)0-, HOCH2-, HOCH(CH3)-,
HO(CH2CH20)4CH2-, HO(CH2CH20)4CH2CH2-, CH30(C=0)0-, CH3CH20(C=0)0-,
(CH3)2C0(C=0)0-, (CH3)3C0(C=0)0-, CH3(C=0)0-, CH3CH2(C=0)0-, (CH3)2C(C=0)0-,
(CH3)3C(C=0)0-, HOCH2(C=0)0-,
HO(CH3)CH(C=0)0-,
HO(CH3)CH(C=0)0(CH3)CH(C=0)0-,
CH3(C=0)0(CH3)CH(C=0)0-,
CH30(C=0)0(CH3)CH(C=0)0-,
CH30(C=0)(CH3)CHO(C=0)0-,
CH3CH20(C=0)(CH3)CHO(C=0)0-,
HOCH2(HOCH2)CHCH20(C=0)0-,
CH3(C=0)0CH2(CH3(C=0)0CH2)CHCH20(C=0)0-,
(CH3)3C(C-0)0CH2((CH3)3C(C-0)0CH2)CHCH20(C-0)0-,
HO(CH3)CH(C=0)0CH2(HO(CH3)CH(C=0)0CH2)CHCH20(C=0)0-,
HSCH2(C=0)0-,
HS(CH3)CH(C=0)0-, HSCH2(NH2)CH(C=0)0-,
HSCH2(CH3(C=0)NH)CH(C=0)0-,
HOOC(NH2)CHCH2CH2(C=0)NH(HSCH2)CH(C=0)NHCH2(C=0)0-,
0(C=0)CH(NE12)CH2CH2(C=0)NHCH(CH2SH)(C=0)NHCH2COOH,
HS(CH3)2C(C=0)NH(SHCH2)CH(C=0)0-,
HOOC(NH2)CHCH2SSCH2CH(NE12)(C=0)0-,
HSCH2(CH3(C=0)NH)CH(C=0)0CH(CH3)(C=0)0-,
-18-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
s-s sis
y0
0
0
HN)C
HOyLl 0
calroy -,,r0 0 S,
NH
0 0
HS , HO 0
or
OH
0
Ox1.1\NO
0 S,s
0
H 0 )SS -rC)1
0
100891 In some embodiments, D comprises: HSCH2(C=0)0-, HS(CH3)CH(C=0)0-,
HSCH2(NH2)CH(C=0)0-,
HSCH2(CH3(C=0)NH)CH(C=0)0-,
HOOC(NH2)CHCH2CH2(C=0)NH(HSCH2)CH(C=0)NHCH2(C=0)0-,
0(C=0)CH(NH2)CH2CH2(C=0)NHCH(CH2SH)(C=0)NHCH2COOH,
HS(CH3)2C(C=0)NH(SHCH2)CH(C=0)0-,
HOOC(NH2)CHCH2SSCH2CH(NH2)(C=0)0-,
HSCH2(CH3(C=0)NH)CH(C=0)0CH(CH3)(C=0)0-,
-19-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
H N )C
8 Hay,..,1
0
cjiyols 0 S,s
S is
a"
)-----µ0 0 HN
'
0 HS , H 0 0-0
,
OH
O\
O .\--D 1\1
0
NH
0 S
HO-..JNA____,,s,s
0 'S
HN s_S 0,/-
0
H 0"--0 ,or 0
=
100901 In some embodiments, D- L' is:
S¨s
HS,ThrO.,r,0,/ HS....ITOTOssos 0,T,0,,s,
0 0 0
, ,
0 0
0
Sis )LNH NH2
OTO/ HS...,...,..1y0..y.0sss FIS....õ,./LT-0,T,0,,ssss
0 0 0
0 0 ''. S H SH
11 0 i 1 0 0 -- H 0
..,}1-..,
HO)*Ly-)1N-.---rN -)L010;\ s's'0-'-'0 N OH
H H N-----ir
H
NH2 0 NH2 0
,
o --SH
cay0TOvs
HS N 0T.xit...
....1r0.,sse
H
HS 0
-20-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
HN
HO
0 S.,
HN
HO 'O 0
OH
0
0 ..y.t0
0
0 S.._ =yfD
H 0 H
0
HN
.S
0
0 HO 0
O
HS N H
0 N H2
0 0
NH2 0 Ly
0
, or
100911 In some embodiments, D is a "keratolytic agent" radical that, upon
release, hydrolysis, or
other mechanism metabolizes or otherwise produces (e.g., when administered to
an individual or
patient, such as in or around the eye, such as the eyelid margin) an active
keratolytic agent (e.g.,
a carboxylic acid and/or a thiol). In some instances, upon release (e.g., by
hydrolysis or other
mechanism), D produces a plurality of active keratolytic agents. In some
instances, the active
keratolytic agent comprises one or more of -SH, -OH, COOH (or C00-), or
disulfide. In some
embodiments, the active keratolytic agent is a carboxylic acid. In some
embodiments, the active
keratolytic agent is selected from the group consisting of acetic acid,
glycolic acid, lactic acid,
lipoic acid, pivalic acid, isobutryic acid, butyric acid, propionic acid,
formic acid, and carbonic
acid. In some embodiments, the active keratolytic agent is a thiol. In some
embodiments, the active
keratolytic agent is a carboxylic acid.
100921 In some embodiments, one or more group of the keratolytic agent (e.g.,
thiol, hydroxy,
carboxylic acid, amide, or amine) is protected or masked (e.g., with
optionally substituted Ci-C6
alkyl (e.g., being optionally substituted with oxo)). In some embodiments, one
or more thiol of
the keratolytic agent is protected or masked with acetyl. In some embodiments,
one or more amine
-21-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
of the keratolytic agent is protected or masked with acetyl. In some
embodiments, one or more
carboxylic acid of the keratolytic agent is protected or masked with methyl,
ethyl, propyl,
isopropyl, or t-butyl. In some embodiments, one or more carboxylic acid of the
keratolytic agent
is protected or masked with ethyl.
100931 In some embodiments, L' is attached to D by a bond.
100941 In some embodiments, any L or linker provided herein comprises one or
more substituted
or un sub sti tuted al koxy (e.g., polyethylene glycol (PEG)).
100951 In some embodiments, any L or linker provided herein comprises a
compound having a
structure of Formula (B):
-(CH2CH20)1X-.
100961 In some embodiments, X is a bond or (C=0). In some embodiments, Xis a
bond. In some
embodiments, X is (C=0).
100971 In some embodiments, b is an integer from 1-20. In some embodiments, b
is an integer
from 1-10. In some embodiments, b is an integer from 1-5. In some embodiments,
b is 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10. In some embodiments, b is 4. In some embodiments, b is
8.
100981 In some embodiments, any L or linker provided herein is attached to the
compound having
a structure of Formula (B).
100991 In some embodiments, the linker is -0(C=0)(OCR8R9)7-. In some
embodiments, z is 1-6.
In some embodiments, Rg is hydrogen or alkyl (e.g., methyl). In some
embodiments, R9 is
hydrogen or alkyl (e.g., methyl). In some embodiments, the linker is -
0(C=0)0CH(CH3)-. In
some embodiments, the linker is -CH(CH3)0(C=0)0- and attached to the compound
having a
structure of Formula (B).
101001 In some embodiments, the linker is -CH(CH3)0(C=0)0- and attached to -
(CH2CH20)4(C=0)-. In some embodiments, the linker is -CH(CH3)0(C=0)0- and
attached to -
(CH2CH20)4-. In some embodiments, the linker is -CH(CH3)0(C=0)0- and attached
to -
(CH2CH20)8(C=0)-. In some embodiments, the linker is -CH(CH3)0(C=0)0- and
attached to -
(CH2CH20)8-.
101011 In some embodiments, the linker is -0(-(C=0)0(CR8R9)z-. In some
embodiments, z is 1-
6. In some embodiments, Rg is hydrogen or alkyl (e.g., methyl). In some
embodiments, R9 is
hydrogen or alkyl (e.g., methyl). In some embodiments, the linker is -
(C=0)0CH2-, -
(C-0)0CH2CH2-, or -(C-0)0CH2CH2CH2-=
101021 In some embodiments, the compound having the structure of Formula (B)
is attached to a
keratolytic agent provided herein (e.g., as described elsewhere herein). In
some embodiments, the
-22-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
compound having the structure of Formula (B) is attached to and includes at
least a portion of a
keratolytic agent provided herein (e.g., as described elsewhere herein).
[0103] In some embodiments, the compound having the structure of Formula (B)
is attached to
any R or R' provided herein (e.g., as described elsewhere herein).
[0104] In certain instances, provided herein is a combination of an anti-
inflammatory (e.g., having
a structure of any formula provided herein, minus the "R" group (e.g., RQ, RN,
etc.)) with a
keratolytic moieity (e.g., being represented by and/or having a structure of
D). In certain
embodiments, such moieties are radicals connected by a linker that is a bond,
with the keratolytic
moiety being hydrolyzable to produce both (1) an anti-inflammatory and (2) one
or more active
keratolytic agent. In some embodiments, such moieties are radicals connected
by a hydrolyzable
linker, with the hydrolyzable linker being hydrolyzable, such that both (1) an
anti-inflammatory
and (2) one or more active keratolytic agent are released (e.g., in vivo, such
as after therapeutic
(e.g., topical) delivery to the eye and/or skin).
101051 In some embodiments, a compound provided herein comprises a first
radical (e.g., a first
radical of Formula I (or any other formula provided herein)) that is dimerized
with a second radical
(e.g., a second radical of Formula I (or any other formula provided herein)).
In some embodiments,
each radical of Formula I (or any other formula provided herein) is dimerized
through an -SH
group thereof (e.g., forming an S-S linkage).
[0106] Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (I'):
R12 0 R2
(R13),
0
R4
R3 0
Formula (I')
101071 In some embodiments, R1 is aryl, cycloalkyl, heterocyclyl, or
heteroaryl, wherein the aryl,
cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted. In some
embodiments, R2, le, and
R4 are each independently H, cyan , halo, ester, alkoxy, alkyl, heteroalkyl,
cycloalkyl or
heterocyclyl, wherein the alkoxy, alkyl, heteroalkyl, cycloalkyl or
heterocyclyl is optionally
substituted. In some embodiments, R12 is -La-Rua, wherein La is a bond, alkyl,
or heteroalkyl, and
R12 is absent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,
wherein the cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is optionally substituted. In some
embodiments, each R13 is
independently H, cyano, halo, alkoxy, alkyl, heteroalkyl, cycloalkyl or
haloalkyl. In some
-23-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
embodiments, n is 0-6. In some embodiments, Lz is bond, -0(C=0)(OCR8R9)7-, or -
(C=0)(OCR8R9)z-. In some embodiments, Lz is bond, -0(C=0)0(CR8R9),-, or -
(C=0)0(CR8R9)z-
. In some embodiments, each R8 and R9 is independently H, halogen, CI-C3-
alkyl, Ci -C3-haloalkyl,
C1-C3-alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms
to which they are
attached to form a C3-05-cycloalkyl. In some embodiments, z is 1-6. In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or
branched) heteroalkyl,
or substituted heterocycloalkyl (e.g., (N-) substituted with alkyl further
substituted with oxo
and/or thiol). In some embodiments, the substituted alkyl is substituted with
one or more (alkyl)
substituent, at least one (alkyl) substituent being independently selected
from the group consisting
of -SH, substituted or unsubstituted (e.g., unsaturated) cycloalkyl, and
dithiolanyl oxide. In some
embodiments, the substituted alkyl is substituted with one or more (alkyl)
substituent, at least one
(alkyl) substituent being independently selected from the group consisting of -
SH and dithiolanyl
oxide. In some embodiments, the substituted heteroalkyl is substituted with
one or more
(heteroalkyl) substituent, at least one (heteroalkyl) substituent being
independently selected from
the group consisting of -SH, -COOH, and thioalkyl, the substituted alkyl. In
some embodiments,
the substituted heteroalkyl, or substituted heterocycloalkyl is further
optionally substituted.
101081 In some embodiments, R1 is optionally substituted aryl, heteroaryl,
cycloalkyl, or
heterocyclyl. In some embodiments, R1 is optionally substituted aryl or
heteroaryl. In some
embodiments, R1 is heteroaryl. In some embodiments, R1 is benzofuran. In some
embodiments,
R1 is
0
101091 In some embodiments, R2 and It4 are each independently H, halo, alkoxy,
or alkyl. In some
embodiments, R2 and R4 are each independently H, halo, or alkyl. In some
embodiments, R2 and
R4 are halo. In some embodiments, R2 and R4 are each independently chloro. In
some
embodiments, R3 is H, alkyl, halo, heteroalkyl, or cycloalkyl. In some
embodiments, R3 is H,
alkyl, or halo. In some embodiments, R3 is H. In some embodiments, le and le
are each
independently chloro and R3 is H.
101101 In some embodiments, La is a bond. In some embodiments, La is a bond
and R12 is an
optionally substituted aryl or heteroaryl. In some embodiments, La is alkyl
and R12 is absent. In
some embodiments, La is alkyl and R12 is optionally substituted aryl or
optionally substituted
heteroaryl. In some embodiments, R12 is optionally substituted aryl,
heteroaryl, aryl-alkyl, or
heteroaryl-alkyl. In some embodiments, R12 is optionally substituted aryl-
alkyl or heteroaryl-
-24-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
alkyl. In some embodiments, R12 is substituted aryl-alkyl or heteroaryl-alkyl.
In some
embodiments, R12 is substituted aryl-alkyl. In some embodiments, R12 is a
sulfonyl substituted
aryl-alkyl. In some embodiments, R12 is a monosulfonyl substituted aryl-alkyl.
In some
embodiments, the sulfonyl substituent is methyl sulfone. In some embodiments,
R12 is
0,1-0
110
[OM] In some embodiments, each R13 is independently H, halo, alkyl,
heteroalkyl, or cycloalkyl.
In some embodiments, each R13 is independently H, halo, or alkyl. In some
embodiments, n is 1
and It1-3 is halo or alkyl. In some embodiments, n is 2 and It1-3 is
independently halo or alkyl. In
some embodiments, n is 0.
101121 In some embodiments, le is heteroaryl, R2 and R4 are each independently
halo, and R1-2 is
a substituted aryl-alkyl. In some embodiments, R1 is heteroaryl, R2 and R4 are
each independently
halo, le is H, R12 is a substituted aryl-alkyl, and n is 0. In some
embodiments, R1 is benzofuran,
R2 and R4 are each independently halo, R3 is H, R12 is a sulfonyl substituted
aryl-alkyl, and n is 0.
In some embodiments, R1 is benzofuran, R2 and R4 are each chloro, R3 is H, R12
is a sulfonyl
mono-substituted aryl-alkyl, and n is 0.
101131 In some embodiments, R1 is:
0
R2 and R4 are each chloro, R3 is H, R12 is:
0,1-0
1101
and n is 0.
101141 Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (Ia):
-25-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0=S=0
0 CI
Lz-O
0
CI 0
0
Formula (Ia)
[0115] In some embodiments, Lz is bond, -(C=0)0(CleR9),-, -0(C=0)(OCR8R9),-,
or -
(C=0)(OCR8R9)z-. In some embodiments, Lz is bond, -0(C=0)(OCR8R9),-, or -
(C=0)(OCR8R9)z-
. In some embodiments, Lz is bond, -0(C=0)0(CR8R9)2-, or -(C=0)0(CR8R9)z-. In
some
embodiments, each R8 and R9 is independently H, halogen, C1-C3-alkyl,
Ci-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are
attached to form a C3-05-cycloalkyl. In some embodiments, z is 1-6. In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or
branched) heteroalkyl,
or substituted heterocycloalkyl (e.g., (N-) substituted with alkyl (e.g.,
further substituted with oxo
and/or thiol)). In some embodiments, the substituted alkyl is substituted with
one or more
substituent, at least one substituent being independently selected from the
group consisting of -
OH, -SH, -COOH, substituted or unsubstituted (e.g., unsaturated) cycloalkyl,
dithiolanyl,
dithiolanyl sulfone, and dithiolanyl oxide. In some embodiments, the
substituted alkyl is
substituted with one or more substituent, at least one substituent being
independently selected
from the group consisting of -SH, substituted or unsubstituted (e.g.,
unsaturated) cycloalkyl, and
dithiolanyl oxide. In some embodiments, the substituted alkyl is substituted
with one or more
substituent, at least one substituent being independently selected from the
group consisting of -
SH and dithiolanyl oxide. In some embodiments, the substituted heteroalkyl is
substituted with
one or more substituent, at least one substituent being independently selected
from the group
consisting of dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide, -SH, -COOH,
and thioalkyl. In
some embodiments, the substituted heteroalkyl is substituted with one or more
substituent, at least
one substituent being independently selected from the group consisting of -SH,
-0001-1, and
thioalkyl. In some embodiments, the substituted alkyl, substituted
heteroalkyl, or substituted
heterocycloalkyl are further optionally substituted. In some embodiments, when
R is alkyl
substituted with dithiolanyl, Lz is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-.
101161 In some embodiments, Lz is bond. In some embodiments, Lz is -
(C=0)(OCR8R9),-. In
some embodiments, Lz is -0(C=0)(OCIVR9)z-. In some embodiments, Lz is -
(C=0)0(CleR9),-.
-26-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
In some embodiments z is 1-3. In some embodiments, z is 1. In some
embodiments, each R.8 and
R9 is independently H or Ci-C3-alkyl. In some embodiments, each le is H and
each R9 is C1-C3-
alkyl. In some embodiments, each IV is H and each R9 is CH3. In some
embodiments, each Rg and
R9 is H. In some embodiments, z is 1, le is H, and R9 is H or CH3.
101171 In some embodiments, LL is -(C=0)0CH(C113)-.
101181 In some embodiments, L is -0(C=0)0CII(CII3)-.
101191 In some embodiments, Lz is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-
101201 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxyl, thiol,
amino, acetamide, -
COOH, substituted unsaturated cycloalkyl (e.g., being substituted with one or
more C1-C4 alkyl),
unsubstituted (saturated) heterocycloalkyl (e.g., dithiolanyl),
and substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl oxide or dithiolanyl sulfone). In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, the (e.g., straight or
branched) alkyl being substituted
with one or more (alkyl) substituent, each (alkyl) substituent being
independently selected from
the group consisting of thiol, amino, acetamide, substituted unsaturated
cycloalkyl (e.g., being
substituted with one or more Ci-C4 alkyl), and substituted heterocycloalkyl
(e.g., dithiolanyl
oxide). In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with hydroxyl. In some embodiments, R is
substituted (e.g.,
straight or branched) alkyl, the (e.g., straight or branched) alkyl being
substituted with -COON.
In some embodiments, R is substituted (e.g., straight or branched) alkyl, the
(e.g., straight or
branched) alkyl being substituted with thiol. In some embodiments, R is
substituted (e.g., straight
or branched) alkyl, the (e.g., straight or branched) alkyl being substituted
with thiol and amide. In
some embodiments, R is substituted (e.g., straight or branched) alkyl, the
(e.g., straight or
branched) alkyl being substituted with thiol and acetamide (e.g., -N(C=0)CH3).
In some
embodiments, R is substituted (e.g., straight or branched) alkyl, the (e.g.,
straight or branched)
alkyl being substituted with 1,2-dithiolanyl oxide. In some embodiments, R is
substituted (e.g.,
straight or branched) alkyl, the (e.g., straight or branched) alkyl being
substituted with 1,2-
dithiolanyl. In some embodiments, R is substituted (e.g., straight or
branched) alkyl, the (e.g.,
straight or branched) alkyl being substituted with 1,2-dithiolanyl sulfone. In
some embodiments,
R is substituted (e.g., straight or branched) alkyl, the (e.g., straight or
branched) alkyl being
-27-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
substituted with substituted unsaturated cycloalkyl (e.g., being substituted
with one or more Ci-
C4 alkyl).
[0121] In some embodiments, L' is bond and R is substituted (e.g., straight or
branched) alkyl,
the (e.g., straight or branched) alkyl being substituted with one or more
(alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting of
hydroxyl, thiol,
amino, acetamide, -COOTT, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more C i-C4 alkyl), unsubstituted (saturated) heterocycloalkyl (e.g., di th i
olanyl), and substituted
(saturated) heterocycloalkyl (e g , dithiolanyl oxide or dithiolanyl sulfone)
[0122] In some embodiments, L' is bond and R is substituted (e.g., straight or
branched) alkyl,
the (e.g., straight or branched) alkyl being substituted with one or more
(alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting of
thiol, amino,
acetamide, substituted unsaturated cycloalkyl (e.g., being substituted with
one or more C1-C4
alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).
[0123] In some embodiments, L' is bond and R is substituted (e.g., straight or
branched) alkyl,
the (e.g., straight or branched) alkyl being substituted with one or more
(alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting of -
OH, -SH, -COOH,
substituted or unsubstituted (e.g., unsaturated) cycloalkyl, dithiolanyl,
dithiolanyl sulfone, and
dithiolanyl oxide.
[0124] In some embodiments, L' is -(C=0)0CH(CH3)- and R is substituted (e.g.,
straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
hydroxyl, thiol, amino, acetamide, -COOH, substituted unsaturated cycloalkyl
(e.g., being
substituted with one or more Ci-C4 alkyl), unsubstituted heterocycloalkyl
(e.g., dithiolanyl), and
substituted heterocycloalkyl (e.g., dithiolanyl oxide or dithiolanyl sulfone).
[0125] In some embodiments, L' is -(C=0)0CH(CH3)- and R is substituted (e.g.,
straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
thiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more Ci-C4 alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).
[0126] In some embodiments, L' is -(C=0)0CH(CH3)- and R is substituted (e.g.,
straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of -
-28-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
OH, -SH, -COOH, substituted or unsubstituted (e.g., unsaturated) cycloalkyl,
dithiolanyl,
dithiolanyl sulfone, and dithiolanyl oxide.
101271 In some embodiments, L' is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-
, and R is substituted (e.g., straight or branched) alkyl, the (e.g., straight
or branched) alkyl being
substituted with one or more (alkyl) substituent, each (alkyl) substituent
being independently
selected from the group consisting of hydroxyl, thiol, amino, acetamide, -
COOII, substituted
unsaturated cycloalkyl (e.g., being substituted with one or more Ci-C4 alkyl),
unsubstituted
heterocycloalkyl (e.g., dithiolanyl), and substituted heterocycloalkyl (e.g.,
dithiolanyl oxide or
dithiolanyl sulfone).
101281 In some embodiments, L' is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-
, and R is substituted (e.g., straight or branched) alkyl, the (e.g., straight
or branched) alkyl being
substituted with one or more (alkyl) substituent, each (alkyl) substituent
being independently
selected from the group consisting of -OH, -SH, -COOH, substituted or
unsubstituted (e.g.,
unsaturated) cycloalkyl, dithiolanyl, dithiolanyl sulfone, and dithiolanyl
oxide.
101291 In some embodiments, R is:
0
S H NH 2
NH
HO
HS}L.ss
H
ss' HO;\ \V)N? 0
0
S¨s NS¨s
0 e
or
101301 In some embodiments, R is:
0
SH N H2 NH
HS H
, or
oe
-29-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101M1 In some embodiments, R is:
HO
[0132] In some embodiments, R is:
HO
101331 In some embodiments, R is:
0
101341 In some embodiments, R is:
HSsf
=
[0135] In some embodiments, R is:
SH
=
[0136] In some embodiments, R is:
NH2
HSJ
,sr
[0137] In some embodiments, R is:
0
}L NH
HSJ
[0138] In some embodiments, R is:
[0139] In some embodiments, R is:
0
Sis
[0140] In some embodiments, R is:
S¨s
-30-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101411 In some embodiments, R is:
¨ o
=
101421 In some embodiments, R is:
0
0,1,
S ¨s
101431 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
101441 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one ester (e.g., within the (e.g., linear or branched) heteroalkyl chain).
101451 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
101461 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one amide (e.g., within the (e.g., linear
or branched)
heteroalkyl chain).
101471 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
101481 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
101491 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and/or one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
101501 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycloalkyl substituted with carboxylic acid). In some embodiments, R is
substituted (e.g.,
-31-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
linear or branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl
being substituted with
one or more (heteroalkyl) substituent, each (heteroalkyl) substituent being
independently selected
from the group consisting of thioalkyl, amino, carboxylic acid, Ci-C6 alkyl,
acetamide, thiol, oxo,
and optionally substituted (e.g., N-attached) heterocycloalkyl (e.g.,
optionally substituted with
carboxylic acid). In some embodiments, R is substituted linear heteroalkyl,
the linear heteroalkyl
being substituted with thioalkyl, amino, and carboxylic acid. In some
embodiments, R is
substituted linear heteroalkyl, the linear heteroalkyl being substituted with
thioalkyl, thiol, and Cl-
C4 alkyl In some embodiments, R is substituted branched heteroalkyl, the
branched heteroalkyl
being substituted with one or more carboxylic acid. In some embodiments, R is
substituted linear
heteroalkyl, the linear heteroalkyl being substituted with heterocycloalkyl
(e.g., dithiolanyl,
dithiolanyl sulfone, dithiolanyl oxide, or N-attached heterocycloalkyl
substituted with carboxylic
acid). In some embodiments, R is substituted linear heteroalkyl, the linear
heteroalkyl being
substituted with dithiolanyl. In some embodiments, R is substituted branched
heteroalkyl, the
branched heteroalkyl being substituted with one or more Ci-C4 alkyl, one or
more oxo, and one
or more N-attached pyrrolidine substituted with carboxylic acid. In some
embodiments, R is
substituted linear heteroalkyl, the linear heteroalkyl being substituted with
amino and carboxylic
acid. In some embodiments, R is substituted linear heteroalkyl, the linear
heteroalkyl being
substituted with thioalkyl. In some embodiments, R is substituted linear
heteroalkyl, the linear
heteroalkyl being substituted with acetamide and carboxylic acid.
101511 In some embodiments, Lz is bond and R is substituted (e.g., linear or
branched) heteroalkyl,
the (e.g., linear or branched) heteroalkyl being substituted with one or more
substituent, each
substituent being independently selected from the group consisting of
thioalkyl, amino, carboxylic
acid, Cl-C6 alkyl, acetamide, thiol, oxo, and optionally substituted (e.g., N-
attached)
heterocycloalkyl (e.g., optionally substituted with carboxylic acid).
101521 In some embodiments, Lz is -(C=0)0CH(CH3)- and R is substituted (e.g.,
linear or
branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl being
substituted with one or more
substituent, each substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycloalkyl substituted with carboxylic acid). In some embodiments, Lz is
-
(C=0)0CH(CH3)- and R is R is substituted linear heteroalkyl, the linear
heteroalkyl being
substituted with dithiolanyl.
-32-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101531 In some embodiments, Lz is -(C=0)0CH(CH3)- and R is substituted (e.g.,
linear or
branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl being
substituted with one or more
substituent, each substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (e.g., N-
attached) heterocycloalkyl (e.g., optionally substituted with carboxylic
acid).
101541 In some embodiments, R is:
S¨s 0
ce S 0
0 ,
0 0 -"SHH 0 '.SHH 0
0 ,õSH
HOAT---ANThiN------;\ ss4-r----ANMIN---)LOH HSKII,N-----ssi
H H
NH2 0 NH2
, 0 H
,
,
0
HN'- 0
HO ,KH isst---",õ.õ.------õ,S,..s..-----.TA.OH
s.
_s r-- HNõTr,-
H
HN/ .11,-N....-., ,S 0
S
0 .,..!.....
HO 0 0 OH
OH
0
Oy-
HS...-.rNH
0 S, 0 NH2
HO -....1.1\1 0 S 0'...-
'0
HOS"-SY )y
NH2
,
0
'ANH 0
HN..,s,Sõ..-Ly "")*L'NH
õ--. HSõ,..),,s
HO 0 ,or
-33-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101551 In some embodiments, R is:
0 0 ='SHH 0 -'-SHH 0
0SH
HOANThr
NH2 0 , NH2 0
OH
0 0
HN)L- 0
HOyLl
0 S,s
0 S,
s --...1_1\1 0
HN HO
,S
HO 0
Oy-
0
HS
NH
0 NH2
)1' 0
0 0 HNs_S NH
HOSS
NH2 HOOHS
or ,
.
101561 In some embodiments, R is:
S¨S
Thi
0
101571 In some embodiments, R is:
0
Oscsss
101581 In some embodiments, R is:
0
H7 HN
0
OOH
-34-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101591 In some embodiments, R is:
xliSHH
0 0
2222,
HO N N
NH2 0 =
101601 In some embodiments, R is:
SH
0 0
SY-)(1\1(E}LOH
NH2 0
101611 In some embodiments, R is:
0 (SH
HS
=
101621 In some embodiments, R is:
0
HN)L-
HO,IrL1
0 S,s
HO 0 =
101631 In some embodiments, R is:
OH
0
0 tO
HO
00 S,
101641 In some embodiments, R is:
0 NH2
HO)Y'S"-Sscs,
NH2
¨35¨
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
101651 In some embodiments, R is:
Oy-
HS
0 0
s.
101661 In some embodiments, R is:
0
)NH
HN
HOO
101671 In some embodiments, R is:
0
--A NH
HSJ
2- .
101681 In some embodiments, R is substituted branched heteroalkyl.
101691 In some embodiments, R is:
0 0
H N HN)L-
HOy1õ1 H 0y1,1
0 S.õs 0 S,s
HO 0 or HO 0
101701 In some embodiments, R-Lz is:
OH
0 0
H 0 1\1-D
HOO y1,1
0 S,s HO 0
0
S,s
0
0
or
101711 In some embodiments, R-Lz is:
-36-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0 S'S s55('0 0 0
0 or
[0172] In some embodiments, R-Lz is:
sk0 0 0
S OH
HNir
0
0
0 OH
[0173] In some embodiments, R is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
further substituted with oxo and/or thiol).
[0174] In some embodiments, R is:
HS 0 , 0 , or
[0175] In some embodiments, R is:
N
HS
[0176] In some embodiments, R is:
0
[0177] In some embodiments, R is:
N-11
0
[0178] In some embodiments, R is:
-37-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0179] In some embodiments, R-Lz is:
0
HS 0 0 I ,
or
0
101801 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
lipoic acid sulfonyl
(Lipsulf), a radical of N-acetyl cysteine (NAC), a radical of cysteine (Cys),
a radical of glutathione
(GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).
101811 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
[0182] In some embodiments, R comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
[0183] In some embodiments, R comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
-38-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
101841 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Laci-, [Lac-
NAC]-, [Cys-Cys]-, [diIILip-NAC-NAC]=, [diIILip-NAC]-, [diIILip-Cap-Cap].,
[diIILip-Cap]-,
RliHLip-Cys-Cys]=, RliHLip-Cys]=, RliHLip-Lipox-Lipox]=, and RliHLip-Lipox]=.
101851 In some embodiments, R is.
ir j.L. xirSH
H
SH NH2 N
HS" ..,_,.\
H S ..L../ HO N
../ .-j./ NH2 " 0
,
0 -.S H 00
sls N / 0
r S H
NThr 'AOH NH2 0 / HS c.)......,,,õ,õ.,,,õ
_.HS \)1N,
H
H
OH
0 0
HN)C 0 .\-1--D
HOõir-H
\r0 0 S s 00 -/¨`)
HO S
HN ,s
s ...i.õ......õõ -..1.1\1 õ...,,,-.., ,S
kT,^-,s,SL,ssE
,-==-..,
HO 'O
Oy-
0
HS,..-...y NH
0 NH2
N H
00
I H N ,...,--
,,s,S
sscsss õ,_õ--1,:ss,
HO)LIS'Src,
,-,-,
NH2 HO 0
,
,
0
><.SN-3,), _KD/
_KS
----µ N / HS
.,...,õ./.õ..,,s
or "Sr .
-39-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101861 In some embodiments, R-Lz is:
i sl
IC) 4 iv 0 4 0 0
-'0
OH OH 0 0 ..--L-.A:)H 0 .),.., A
0OH ,
4
0 0 NH2
)._(:),..1-L...-.1r0H 0
HS-r(:)TC)y HS-(CITC)), HS I0
o
--A- NH ilD 0 40
S¨S
HS0 0õ L.,,...o
'1
s 0
0 0
540 0 /0 0 e S'o o
0,,Ko
sxo Lo
s,s
's
Lo Lo s
e
o
Ao o S Is
Sõ0 OTO/
LO S
, or 0 .
101871 Tn some embodiments, R-T,' is.
NH2
õ,,
HS---y '-1 --sy Hs(0 0 HS 0 õss ----
Lir --/--0 ,s,
0 0 0 ,
,-SH
,..SH
0 0 0
0
H i 0 0 H
H 0)Y)( N Thr N0 1 0")\ ss5-0-
1 0
N...11-- N --')LOH
H H
NH2 0 NH2 0
,
0
0
S Is NClay0T-0,/ 0 '"SH
OTO,/ )---ko HS 0 HS xl,
N ---yoTav
H
0 0
,
,
-40-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
H N
Hai(LI
0 S,s
H N
H 0 0 0
OH
0
0 .\",,r,-D
0 s,s
H 0 0 0 N
H2
HO)YS'r(Dy(DY
o N
H2 0
Oy
H S H 0
0
')( NH
0 0
o H N ,S
0 H 0 0 0
1111.r.0 O., <5 (O
O.,
00 Ts" TssrNOTO
0
NH
0
-41 -
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0188] In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (lb):
0=S=0
0 CI
,Lz-0
Rx
0
CI 0
0
Formula (Ib).
[0189] In some embodiments, L' is bond or -(C=0)(OCR8R9)z-. In some
embodiments, each R8
and R9 is independently H, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-
alkoxy, C3-05-
cycloalkyl, or R8 and R9 are taken together with the atoms to which they are
attached to form a
C3-05-cycloalkyl. In some embodiments, z is 1-6.
[0190] In some embodiments, IV is:
R2a R2b R2c Rzd
R1as ms/
eop.2
o
Ribs
R2f
[0191] In some embodiments, Rla and Rib are each independently -H or -SR'. In
some
embodiments, each R1 is independently substituted or unsubstituted (e.g.,
straight or branched)
alkyl or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl. In some embodiments,
each R2a, R2b, R2c, R2d, R2e, and R2f is independently H, halogen, C1-C3-
alkyl, Ci -C3-haloalkyl,
C1-C3-alkoxy, C3-05-cycloalkyl, or two of R2a and R2b, R2' and R2d, or R2' and
R2f are taken
together with the atoms to which they are attached to form a C3-05-cycloalkyl.
In some
embodiments, m is an integer from 1-10. In some embodiments, n and o are each
independently
an integer from 0-3.
[0192] In some embodiments, L', le, R9, and z are each described elsewhere
herein.
[0193] In some embodiments, n and o are each independently 0 or 1. In some
embodiments, n is
0 or 1. In some embodiments, n is 1. In some embodiments, o is 0 or 1. In some
embodiments, o
is 0. In some embodiments, n is 0 and n is 1.
101941 In some embodiments, m is 3-5. In some embodiments, m is 4. In some
embodiments, n is
0 and m is 4. In some embodiments, n is 1 and m is 4. In some embodiments, n
is 0, n is 1, and m
is 4.
-42-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
101951 In some embodiments, each R2', R2b, R2c, R2d, R2c, and R21- is
independently H, halogen,
e
C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, each R2 R2b R2c R2d R2
a , , , , , and R2f is
independently H, halogen, Ci-Clalkyl, or Ci -C3haloalkyl, at least one of R2a,
R2b, R2c, R2d, R2e,
and R2f being halogen, C1-C3alkyl, or C1-C3haloa1kyl. In some embodiments,
each R2a, R2b, R2c,
R2d, R2e, and R2f is H.
101961 In some embodiments, IV is:
SRlb
R1 as sss
101971 In some embodiments, Ria and Rib are each independently -H or -SR'. In
some
embodiments, each Ric is independently substituted or unsubstituted (e.g.,
straight or branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being
independently selected from the group consisting of carboxylic acid, -SH,
thioalkyl, acetamide,
amino, oxo, optionally substituted heterocycloalkyl (e.g., N-attached
pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted
with one or more (heteroalkyl) substituent, each (heteroalkyl) substituent
being independently
selected from the group consisting of carboxylic acid, amino, thioalkyl,
thiol, acetamide, and Ci-
C3 alkyl).
101981 In some embodiments, Itla is -H or -SRI' and Rib is -SRI', or Rla is -
SRI' and Rib is -H or
-SW'. In some embodiments, Rla is -II or -SW' and Rib is -SR''. In some
embodiments, Rla is -II
and Rib is -SR'. In some embodiments, Rla is -SR and Rib is -H or -SR'. In
some embodiments,
Ria is -SR' and Rth is -SR'. In some embodiments, Ria and Rth are each -SR'.
101991 In some embodiments, Ria and Rib each independently comprise a radical
of one or more
keratolytic group (e.g., each radical of the one or more keratolytic group
being independently
selected from the group consisting of a radical of glycolic acid (GA), a
radical of thioglycolic acid
(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a
radical of lipoic acid
(Lip), a radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic
acid (diHLip), a radical
of N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of
glutathione (GSH), a radical
of captopril (Cap), and a radical of bucillamine (Buc)).
102001 In some embodiments, Rh and Rib are each independently a radical of one
or more
keratolytic group, each radical of the one or more keratolytic group being
independently selected
from the group consisting of a radical of glycolic acid (GA), a radical of
thioglycolic acid (TGA),
a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a radical
of lipoic acid (Lip), a
radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic acid
(diHLip), a radical of N-
-43 -
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of glutathione
(GSH), a radical of
captopril (Cap), and a radical of bucillamine (Buc).
102011 In some embodiments, Rh and Rib each independently comprise a (thiol)
radical of one or
more keratolytic group, each (thiol) radical of the one or more keratolytic
group being
independently selected from the group consisting of a (thiol) radical of
thioglycolic acid (TGA),
a (thiol) radical of thiolactic acid (TLac), a (thiol) radical of
dihydrolipoic acid (diIILip), a (thiol)
radical of N-acetyl cysteine (NAC), a (thiol) radical of cysteine (Cys), a
(thiol) radical of
glutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol) radical
of bucillamine (Buc)
102021 In some embodiments, R' and Rth are each independently a thiol radical
of one or more
keratolytic group, each thiol radical of the one or more keratolytic group
being independently
selected from the group consisting of a thiol radical of thioglycolic acid
(TGA), a thiol radical of
thiolactic acid (TLac), a thiol radical of dihydrolipoic acid (diHLip), a
thiol radical of N-acetyl
cysteine (NAC), a thiol radical of cysteine (Cys), a thiol radical of
glutathione (GSH), a thiol
radical of captopril (Cap), and a thiol radical of bucillamine (Buc).
102031 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Laci-, [Lac-
NAC] [Cy s-Cy s] [diHLip-NAC
[diHLip-NAC]., [diElLip-C ap-C ap]., [diHLip-Cap].,
[diHLip-Cys-Cys]-, [diHLip-Cys]-, [diHLip-Lipox-Lipox]-, and [diHLip-Lipox]...
102041 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of R" and/or Rib to the rest of the molecule. In some embodiments, (the thiol
radical of) R" and/or
Rib each independently attach to the rest of the molecule to form a disulfide
bond.
102051 In some embodiments, Ria and Rth are each independently -H or:
-44-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
s&s
HS
sisfS
, OHOH SOH HS
OH
Thr
0
cly.ON
1
)LNH NH2 0 0 0
0
OH S
oY-
1
0 '..SH
0 0 0
0 0 , or 0
102061 In some embodiments, Ria and Rib are the same. In some embodiments, Ria
and Rib are
each -SR and the same. In some embodiments, Ria and Rib are different. In some
embodiments,
R a and Rib are each SR' and different.
102071 In some embodiments, LL is -(C=0)0CH(CH3)-, and IV is:
Ries,
R1CsScs.s51
102081 In some embodiments, each Ric is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or un sub stituted (e.g., straight or
branched) heteroalkyl. In some
embodiments, each Ric is independently substituted (e.g., straight or
branched) alkyl or substituted
(e.g., straight or branched) heteroalkyl. In some embodiments, each R' is
independently
substituted (e.g., straight or branched) alkyl. In some embodiments, each Ric
is (the same)
substituted (e.g., straight or branched) alkyl. In some embodiments, each Ric
is (a different)
substituted (e.g., straight or branched) alkyl.
102091 In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
heteroalkyl. In some embodiments, each Ric is (the same) substituted (e.g.,
straight or branched)
heteroalkyl. In some embodiments, each Ric is (a different) substituted (e.g.,
straight or branched)
heteroalkyl.
102101 In some embodiments, one of R' is substituted (e.g., straight or
branched) alkyl and the
other is substituted (e.g., straight or branched) heteroalkyl.
-45-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0211] In some embodiments, each R1c is the same. In some embodiments, each
R1c is different.
[0212] In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl)
substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl (e.g., -CH2SH), acetamide (e.g., -NH(C=0)CH3), amino, oxo, and
optionally substituted
heterocycl alkyl (e.g., N-attached pyrroli di nyl substituted with -C 00I I).
[0213] In some embodiments, the optionally substituted heterocycloalkyl is:
OH
[0214] In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
substituent, each (heteroalkyl) substituent being independently selected from
the group consisting
of carboxylic acid, amino, thioalkyl (e.g., -CH2SH), thiol, acetamide (e.g., -
NH(C=0)CH3), and
Cl-C3 alkyl.
[0215] In some embodiments, Ric is:
\oHHS
_.ThrOH OH Hs OH
0
-)L NH NH2 0 0 0 cay0H
iss),y0H
HO-rity--)LN OH
0
Oy
r--xNH
SH
0 0
tx.jt, õ-C1r0H HS7\5-.,NOH
0 0 , or 0
[0216] In some embodiments, Rla, Rib, and each Ric each independently comprise
one or more
substituent that is a carboxylic acid or an ester. In some embodiments, 10,
Rth, and each It each
each independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H).
In some embodiments, Rla comprises one or more substituent that is a
carboxylic acid (e.g., -
(C=0)0H). In some embodiments, Itth comprises one or more substituent that is
a carboxylic acid
-46-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
(e.g., -(C=0)0H). In some embodiments, each Rle independently comprises one or
more
substituent that is a carboxylic acid (e.g., -(C=0)0H). In some embodiments,
Rla, Rib, and each
Ric each independently comprise one or more substituent that is an ester
(e.g., -(C=0)0-C1-
C4alkyl). In some embodiments, Rla comprises one or more substituent that is
an ester (e.g., -
(C=0)0-CI-C4alkyl). In some embodiments, Rib comprises one or more substituent
that is an ester
(e.g., -(C=0)0-Ci-C4alkyl). In some embodiments, each Ric independently
comprises one or more
substituent that is an ester (e.g., -(C=0)0-Ci-C4alkyl).
102171 In some embodiments, the -(C=0)0H of Rut, Ru), and/or RI is optionally
esterified (e g ,
-(C=0)0H or -(C=0)0-Ci-C4alkyl). In some embodiments, the Cl-C4alkyl is
methyl, ethyl,
propyl, isopropyl, butyl, or t-butyl.
102181 In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (Ic):
0=S=0
0 CI
RY
0
CI 0
0
Formula (Ic).
102191 In some embodiments, L7 is bond or -(C=0)(OCR8R9)z-. In some
embodiments, each R8
and R9 is independently H, halogen, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-
alkoxy, C3-05-
cycloalkyl, or le and R9 are taken together with the atoms to which they are
attached to form a
C3-05-cycloalkyl. In some embodiments, z is 1-6.
102201 In some embodiments, Lz, R8, R9, and z are each described elsewhere
herein.
[0221] In some embodiments, RY is:
R4 a R4 b
e s
P
[0222] In some embodiments, each R4a and R4b is independently H, halogen, or
substituted or
unsubstituted alkyl. In some embodiments, p is an integer from 1-10. In some
embodiments, q is
an integer from 1-3.
-47-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
102231 In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some
embodiments, p
is an integer from 3-5. In some embodiments, p is 4. In some embodiments, q is
1 and p is 4.
102241 In some embodiments, each R4a and R4b is independently H or substituted
or unsubstituted
alkyl. In some embodiments, each R4a and R4b is independently H, halogen, C1-
C3alkyl, or Ct-
C3haloalkyl. In some embodiments, each R4a and R4b is H.
102251 In some embodiments, q is 1, p is an integer from 3-5, and each R4 and
R4b is
independently H, halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments,
q is 1, p is 4, and
each R4a and R4b is H
102261 In some embodiments, Lz is -(C=0)0CH(CH3)-, and RY is:
oe
/.
102271 In some embodiments, provided herein is a compound having the structure
of Formula
(Id):
1
0=S=0
0 CI
,Lz-0
RY
0
CI 0
0
Formula (Id).
102281 In some embodiments, Lz is bond or -(C=0)(OCR8R9)z-. In some
embodiments, each R8
and R9 is independently H, halogen, C1-C3-alkyl, Ci-C3-haloalkyl, C1-C3-
alkoxy, C3-05-
cycloalkyl, or R8 and R9 are taken together with the atoms to which they are
attached to form a
C3-05-cycloalkyl. In some embodiments, z is 1-6.
102291 In some embodiments, Lz, le, R9, and z are each described elsewhere
herein.
102301 In some embodiments, It' is:
NR6R7
R113 R11
-48-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
102311 In some embodiments, R5 is -SR'. In some embodiments, Rlc is
substituted or
unsubstituted (e.g., straight or branched) alkyl (e.g., substituted with one
or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl
(e.g., N-attached pyrrolidinyl substituted with -COOH)) or substituted or
unsubstituted (e.g.,
straight or branched) heteroalkyl (e.g., substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of carboxylic
acid, amino, thioalkyl, thiol, acetamide, and C1-C3 alkyl). In some
embodiments, R6 and R7 are
each independently H, substituted or unsubstituted alkyl, or substituted or
unsubstituted
heteroalkyl. In some embodiments, each le and R11 is independently H,
halogen, CI-C3-alkyl,
C1-C3-haloalkyl, C1-C3-alkoxy, C3-05-cycloalkyl, or two or more of Rth and R"
are taken together
with the atoms to which they are attached to form a C3-05-cycloalkyl. In some
embodiments, s is
an integer from 1-10.
102321 In some embodiments, R6 and R7 are each independently H or substituted
or unsubstituted
alkyl (e.g., Cl-C3 alkyl optionally substituted with oxo). In some
embodiments, R6 and R7 are each
independently H or Ci-C3 alkyl optionally substituted with oxo. In some
embodiments, R6 and R7
are each independently H or -(C=0)CH3. In some embodiments, R6 is H and R7 is
H or -
(C=0)CH3. In some embodiments, R6 is H and R7 is -(C=0)CH3. In some
embodiments, R6 and
R7 are H.
102331 In some embodiments, each Rl and R" is independently H, halogen, C1-
C3alkyl, or C1-
C3haloalkyl . In some embodiments, each Rl and RI' is H.
102341 In some embodiments, s is 1-3. In some embodiments, s is 1. In some
embodiments, s is 1
and Rm and R11 are H.
102351 In some embodiments, R5 comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
102361 In some embodiments, R5 is a radical of one or more keratolytic group,
each radical of the
one or more keratolytic group being independently selected from the group
consisting of a radical
of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical of
lactic acid (Lac), a radical
-49-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical of lipoic
acid sulfoxide (Lipox),
a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine
(NAC), a radical of cysteine
(Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a
radical of bucillamine
(Buc).
102371 In some embodiments, R5 comprises a (thiol) radical of one or more
keratolytic group,
each (thiol) radical of the one or more keratolytic group being independently
selected from the
group consisting of a (thiol) radical of thioglycolic acid (TGA), a (thiol)
radical of thiolactic acid
(TLac), a (thiol) radical of dihydrolipoic acid (diHLip), a (thiol) radical of
N-acetyl cysteine
(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical of glutathione
(GSH), a (thiol) radical
of captopril (Cap), and a (thiol) radical of bucillamine (Buc).
102381 In some embodiments R5 is a thiol radical of one or more keratolytic
group, each thiol
radical of the one or more keratolytic group being independently selected from
the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
102391 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]-, [Lac-
NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC]., [diHLip-NAC]=, [difiLip-Cap-Cap].,
[diHLip-Cap]=,
[diHLip-Cys-Cys]., [diHLip-Cys]., [diHLip-Lipox-Lipox]=, and [diHLip-Lipox]...
102401 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of R5 to the rest of the molecule. In some embodiments, R5 attaches to the
rest of the molecule to
form a disulfide bond.
102411 In some embodiments, R5 is:
-50-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
s&s
HS
sisfS
, OHOH SOH HS OH
Thr
0 cly-
OH
)L NH N H2 0 0 0
0
S OH S OH H N
OH S
oY-
SH
0 0 0 0
\?, S N H HSNOH
0 0 , or 0
102421 In some embodiments, Rz is:
NHR7
S
R1 CS
Sfj-
102431 In some embodiments, R7 is H or -(C=0)CH3. In some embodiments, R7 is
H. In some
embodiments, R7 is -(C=0)CH3
102441 In some embodiments, R1c is described elsewhere herein.
102451 In some embodiments, R5 comprises one or more substituent that is a
carboxylic acid or
an ester. In some embodiments, le comprises one or more substituent that is a
carboxylic acid
(e.g., -(C=0)0H). In some embodiments, R5 comprises one or more substituent
that is an ester
(e.g., -(C=0)0-C i-C4alkyl).
102461 In some embodiments, the -(C=0)0H of R5 is optionally esterified (e.g.,
-(C0)OH or -
(C=0)0-Ci-C4alkyl). In some embodiments, the Ci-C4alky1 is methyl, ethyl,
propyl, isopropyl,
butyl, or t-butyl.
102471 In some embodiments, provided herein is a pharmaceutical composition
comprising any
compound provided herein, such as a compound represented by any one of Formula
(I), Formula
(I'), Formula (I), Formula (Ia), Formula (lb), Formula (Ic), Formula (Id),
Formula (I-A), Formula
(I-B), Formula (I-C), Table 1, Table 2, or a pharmaceutically acceptable salt
thereof, or a
pharmaceutically acceptable salt thereof, and at least one pharmaceutically
acceptable excipient.
In some embodiments, the pharmaceutical composition is suitable for ophthalmic
administration.
-51-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
In some embodiments, the pharmaceutical composition is suitable for topical
ophthalmic
administration. In some embodiments, topical ophthalmic administration is
administration in
and/or around the eye, such as to the eyelid margin. In some embodiments,
topical ophthalmic
administration is administration to the ocular surface and the inner surface
to the eyelid.
102481 In some embodiments, a compound or a pharmaceutical composition
comprising any
compound provided herein, such as a compound of any one of Formula (I),
Formula (I'), Formula
(I), Formula (Ia), Formula (lb), Formula (Ic), Formula (Id), Formula (I-A),
Formula (T-B),
Formula (I-C), Table 1, Table 2, or a pharmaceutically acceptable salt
thereof, is substantially
hydrolytically stable (e.g., stable in an aqueous composition (e.g.,
solution), such as a buffer
solution or ophthalmically acceptable aqueous composition). In some
embodiments, the
compound or the pharmaceutical composition is formulated in an aqueous
vehicle. In some
embodiments, the compound or the pharmaceutical composition is formulated and
stored in an
aqueous vehicle. In some instances, compositions or formulations provided
herein are chemically
and/or physically stable in an aqueous composition.
102491 In some embodiments, a compound provided herein, such as a compound of
any one of
Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula
(Ic), Foimula (Id),
Formula (I-A), Formula (I-B), Formula (I-C), Table 1, Table 2, or a
pharmaceutically acceptable
salt thereof, is reduced to one or more keratolytic agent (e.g., a free form
of a radical of Formula
(I), Formula (I'), Formula (I), Formula (Ia), Formula (Ib), Formula (Ic),
Formula (Id), Formula (I-
A), Formula (I-B), Formula (I-C), or Table 1, Table 2, such as wherein R is a
negative charge or
H) and/or hydrolyzed to an active pharmaceutical agent(e.g., a free form of a
radical of Formula
(I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula (Ic),
Formula (Id), Formula (I-
A), Formula (T-B), Formula (I-C), or Table 1, Table 2, such as wherein R is a
negative charge or
H). In some embodiments, the compound or pharmaceutical composition is reduced
to one or
more keratolytic agent in an ocular space. In some embodiments, the compound
or pharmaceutical
composition is reduced to one or more keratolytic agent by a reductase in an
ocular space.
102501 In some embodiments, a compound provided herein, such as a compound of
any one of
Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula
(Ic), Formula (Id),
Formula (I-A), Formula (T-B), Formula (I-C), Table 1, Table 2,or a
pharmaceutically acceptable
salt thereof, is hydrolyzed to an active pharmaceutical agent (e.g., a free
form of a radical of
Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula
(Ic), Formula (Id),
Formula (I-A), Formula (T-B), Formula (I-C), or Table 1, Table 2, such as
wherein R is a negative
charge or H) and a keratolytic agent. In some embodiments, the compound or
pharmaceutical
-52-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
composition is hydrolyzed to an active pharmaceutical agent and a keratolytic
agent in an ocular
space. In some embodiments, the compound or pharmaceutical composition is
hydrolyzed to an
active pharmaceutical agent and a keratolytic agent by an esterase in an
ocular space. In some
embodiments, the active pharmaceutical agent is an anti-inflammatory agent. In
some
embodiments the anti-inflammatory agent is Lifitegrast. In some embodiments,
the keratolytic
agent is a carboxylic acid. In some embodiments, the carboxylic acid is
selected from the group
consisting of acetic acid, glycolic acid, lactic acid, li poi c acid, pi val i
c acid, isobutryic acid, butyric
acid, propionic acid, formic acid, and carbonic acid In some embodiments, the
active keratolytic
agent is a thiol.
102511 In some embodiments, a compound or a pharmaceutical composition
comprising any
compound provided herein, such as a compound of any one of Formula (I),
Formula (I'), Formula
(I), Formula (Ia), Formula (lb), Formula (Ic), Formula (Id), Formula (I-A),
Formula (I-B),
Formula (I-C), Table 1, Table 2, or a pharmaceutically acceptable salt
thereof. In certain
embodiments, the composition further comprises an amount of a free form of a
radical of any of
Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula
(Ic), Formula (Id),
Formula (I-A), Formula (T-B), Formula (I-C), Table 1, Table 2, or the like
(such as wherein the
free form is the radical, wherein R is a negative charge or an H). In some
embodiments, a
composition provided herein comprises a (e.g., weight or molar) ratio of a
compound provided
herein to a free form of a radical of Formula (I), Formula (I'), Formula (I),
Formula (Ia), Formula
(Ib), Formula (Ic), Formula (Id), Formula (I-A), Formula (I-B), Formula (I-C),
Table 1, Table 2,
or a pharmaceutically acceptable salt thereof (e.g., wherein R is a negative
charge or an H) is about
1:99 to about 100:0 (e.g., the amount of the free form of the radical relative
to the overall amount
of free form of the radical plus the conjugate is between 0% (weight or molar)
and 99%). In some
embodiments, the relative amount of the free form of the radical is 0% to
about 50%, such 0% to
about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1 % to about 5%,
less than 5%,
less than 2.5%, less than 2%, or the like (percentages being weight/weight or
mole/mole
percentages). In some instances, such aqueous compositions are pre-
manufactured or are
manufactured at the time of application in order to maintain high
concentrations of the compound
relative to the free form of a radical thereof In some embodiments, such
concentrations of the
compound are present in the composition for at least 45 minutes in an aqueous
composition (such
as in an aqueous composition, e.g., a HEPES buffer, such as under the
conditions described herein,
such as in Table 3 and Table 4). Table 3 and Table 4 of the Examples
illustrate good stability of
the compositions provided herein and such recitations are incorporated in the
disclosure hereof.
-53-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Further, in some instances, compounds provided herein release free form of a
radical of a
compound of Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula
(lb), Formula (Ic),
Formula (Id), Formula (I-A), Formula (I-B), Formula (I-C), or Table 1, Table
2, (e.g., wherein R
is a negative charge or H), such as when administered to an individual (e.g.,
ocular (e.g., pen-
ocular) or dermatological administration). In more specific instances, when
administered to an
individual at a location with esterases and/or reductases present, rapid
release of active (free)
forms of a radical of Formula (I), Formula (I'), Formula (I), Formula (Ia),
Formula (lb), Formula
(Ic), Formula (Id), Formula (I-A), Formula (I-B), Formula (I-C), or Table 1,
Table 2, (e g , wherein
R is a negative charge or H) (and, a keratolytic agent and/or agent that
further produces active
keratolytic agent(s) (e.g., by further hydrolysis and/or reduction thereof)).
102521 In some embodiments, provided herein a compound or a pharmaceutical
composition
comprising any compound provided herein, such as a compound of any one of
Formula (I),
Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula (Ic), Formula
(Id), Formula (I-A),
Formula (T-B), Formula (I-C), Table 1, Table 2, or a pharmaceutically
acceptable salt thereof, has
keratolytic effects (e.g., reduces disulfide (S-S) bonds) (e.g., in any
environment provided herein).
102531 Provided in some embodiments herein is a method of treating
inflammation and/or
hyperkeratosis, the method comprising administering to an individual (e.g., in
need thereof) any
compound provided herein (e.g., of any Formula or Table provided herein)
(e.g., in a
therapeutically effective amount). In specific embodiments, the inflammation
and/or
hyperkeratosis is inflammation and/or hyperkeratosis of the eye, periocular
structures (e.g.,
eyelid), and/or skin.
102541 Provided in some embodiments herein is a method of treating a
dermatological or an
ophthalmic disease or disorder in an individual in need of thereof, comprising
administering to
the individual in need thereof a composition comprising any compound provided
herein, such as
a compound represented by any one of Formula (I), Formula (I'), Formula (I),
Formula (Ia),
Formula (lb), Formula (Ic), Formula (Id), Formula (I-A), Formula (T-B),
Formula (I-C), Table 1,
Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments,
the dermatological
or ophthalmic disease or disorder is inflammation or hyperkeratosis of the
eyes or skin (e.g., the
ocular surface). In some embodiments, the dermatological or ophthalmic
dermatological disease
or disorder is selected from the group consisting of meibomian gland
dysfunction (MGD), dry eye
disease (DED), ocular manifestations of graft versus host disease, vernal
keratoconjunctivitis,
atopic keratoconjunctivitis, Cornelia de Lange Syndrome, evaporative eye
disease, aqueous
deficiency dry eye, blepharitis, and seborrheic blepharitis. In some
embodiments, the
-54-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
dermatological or ophthalmic disease or disorder is inflammation or
hyperkeratosis (e.g., of the
eyes or skin), such as, for example, meibomian gland dysfunction (MGD), dry
eye disease (DED),
ocular manifestations of graft versus host disease, vernal
keratoconjunctivitis, atopic
keratoconjunctivitis, Cornelia de Lange Syndrome, evaporative eye disease,
aqueous deficiency
dry eye, blepharitis, seborrheic blepharitis, or any combination thereof
102551 In some embodiments, the ophthalmic disease or disorder is selected
from dry eye, lid
wiper epitheliopathy (LWE), contact lens discomfort (CLD), contact lens
discomfort, dry eye
syndrome, evaporative dry eye syndrome, aqueous deficiency dry eye syndrome,
blepharitis,
keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland
disorder, inflammation of
the anterior surface of the eye, infection of the anterior surface of the eye,
infection of the lid,
demodex lid infestation, lid wiper epitheliopathy and autoimmune disorder of
the anterior surface
of the eye.
102561 In some embodiments, provided herein is a method of treating an ocular
(e.g., pen-ocular)
or dermatological indication (e.g., associated with keratolytic activity,
inflammation, and/or
microbial infiltration), the method comprising administering a therapeutically
effective amount of
a compound or composition provided herein. In some embodiments, a composition
provided
herein (e.g., used in a method provided herein) comprises a compound provided
herein in a
therapeutically effective amount (e.g., at a concentration effective to treat
keratosis/keratolytic
activity, inflammation, and/or microbial infiltration), in the eye,
surrounding tissue, or skin. In
some embodiments, a (e.g., pharmaceutical and/or ophthalmic) composition
provided herein
comprises about 0.1 wt. % to about 10 wt % of a compound provided herein.
102571 In some embodiments, ocular and/or dermatological disorders include,
for example,
inflammatory conditions of the eyelids (e.g., hordeolum (stye), blepharitis,
and chalazion), ocular
surface (e.g.,dry eye disease and anterior uveitis) and posterior eye (e.g.,
posterior and pan-
uveitis), abnormalities of the pen-ocular glands (e.g., meibomian gland
dysfunction (MGD)),
allergic-type conditions, (e.g., eczema, atopic dermatitis, atopic
keratoconjunctivitis refractory to
topical steroid treatment, and vernal keratoconjunctivitis), surgical
complications (e.g., corneal
transplant rejection, post-corneal transplant glaucoma, cataracts secondary to
phakic corneal
transplant, fungal infections in keratoplasty patients, and post-LASIK dry eye
and/or poor
refractive outcomes), corneal abnormalities (e.g., inflammatory corneal
ulceration, rheumatoid
corneal ulcers, and Thygeson's superficial punctate keratitis), conjunctival
abnormalities (e.g.,
iridocyclitis, ligneous conjunctivitis), ocular complications from systemic
treatments and/or
autoimmune diseases (e.g., pauciarticular juvenile rheumatoid arthritis, graft
versus host disease,
-55-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
and sjogren's syndrome) and/or infectious disease of the anterior surface of
the eye. In some
embodiments, provided herein are compositions and methods for the treatment of
ocular and
periocular abnormalities that have multifactorial etiologies and interactions.
INCORPORATION BY REFERENCE
102581 All publications, patents, and patent applications mentioned in this
specification are herein
incorporated by reference for the specific purpose identified herein.
DETAILED DESCRIPTION
Certain Definitions
102591 As used herein and in the appended claims, the singular forms "a,"
"and," and "the" include
plural referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an
agent" includes a plurality of such agents, and reference to the cell"
includes reference to one or
more cells (or to a plurality of cells) and equivalents thereof, and so forth.
When ranges are used
herein for physical properties, such as molecular weight, or chemical
properties, such as chemical
formulae, all combinations and subcombinations of ranges and specific
embodiments therein are
intended to be included. The term "about" when referring to a number or a
numerical range means
that the number or numerical range referred to is an approximation within
experimental variability
(or within statistical experimental error), and thus the number or numerical
range may vary from
1% and 15% of the stated number or numerical range. The term "comprising" (and
related terms
such as "comprise" or "comprises" or "having" or "including") is not intended
to exclude that in
other certain embodiments, for example, an embodiment of any composition of
matter,
composition, method, or process, or the like, described herein, may "consist
of' or "consist
essentially of' the described features.
102601 The terms "treat," "treating," or "treatment" as used herein, include
reducing, alleviating,
abating, ameliorating, relieving, or lessening the symptoms associated with a
disease, disease sate,
or indication (e.g., addiction, such as opioid addiction, or pain) in either a
chronic or acute
therapeutic scenario. Also, treatment of a disease or disease state described
herein includes the
disclosure of use of such compound or composition for the treatment of such
disease, disease state,
or indication.
102611 "Amino" refers to the ¨NH2 radical.
102621 "Cyano- refers to the -CN radical.
102631 "Nitro" refers to the -NO2 radical.
102641 "Oxo" refers to the =0 radical.
-56-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
102651 "Alkyl" generally refers to a straight or branched hydrocarbon chain
radical consisting
solely of carbon and hydrogen atoms, such as having from one to fifteen carbon
atoms (e.g., C1-
C15 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g.,
an alkenyl, which
comprises at least one carbon-carbon double bond). Disclosures provided herein
of an -alkyl" are
intended to include independent recitations of a saturated "alkyl," unless
otherwise stated. Alkyl
groups described herein are generally monovalent, but may also be divalent
(which may also be
described herein as "alkyl ene" or "alkyl enyl" groups). In certain
embodiments, an alkyl comprises
one to thirteen carbon atoms (e.g., C1-C13 alkyl) In certain embodiments, an
alkyl comprises one
to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl
comprises one to five
carbon atoms (e.g., Ci-05 alkyl). In other embodiments, an alkyl comprises one
to four carbon
atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to
three carbon atoms
(e.g., Ci-C3 alkyl). In other embodiments, an alkyl comprises one to two
carbon atoms (e.g., C1-
C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci
alkyl). In other
embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15
alkyl). In other
embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8
alkyl). In other
embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-05 alkyl).
In other
embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-05
alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-
propyl), 1-methylethyl
(iso-propyl), 1-butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl
(iso-butyl),
1, 1 -dimethylethyl (tert-butyl), 1 -pentyl (n-pentyl). The alkyl is attached
to the rest of the molecule
by a single bond. In general, alkyl groups are each independently substituted
or unsubstituted.
Each recitation of "alkyl" provided herein, unless otherwise stated, includes
a specific and explicit
recitation of an unsaturated "alkyl" group. Similarly, unless stated otherwise
specifically in the
specification, an alkyl group is optionally substituted by one or more of the
following substituents:
halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR', -SR', -
0C(0)-Ra, -N(Ra)2, -
C(0)Ra, -C(0)0Ra, -C(0)N(Ra)2, -N(Ra)C(0)0Ra, -0C(0)-N(Ra)2, -N(Ra)C(0)Ra, -
N(Ra)S(0)tRa
(where t is 1 or 2), -S(0)OR' (where t is 1 or 2), -S(0)tRa (where t is 1 or
2) and -S(0)tN(Ita)2
(where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally
substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl
(optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl
(optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally
substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with
halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with
halogen, hydroxy,
-57-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with
halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen,
hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl).
102661 "Alkoxy" refers to a radical bonded through an oxygen atom of the
formula ¨0-alkyl,
where alkyl is an alkyl chain as defined above.
102671 "Alkenyl" refers to a straight or branched hydrocarbon chain radical
group consisting
solely of carbon and hydrogen atoms, containing at least one carbon-carbon
double bond, and
having from two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to
eight carbon atoms. In other embodiments, an alkenyl comprises two to four
carbon atoms. The
alkenyl is optionally substituted as described for "alkyl" groups.
102681 "Alkylene or "alkylene chain- generally refers to a straight or
branched divalent alkyl
group linking the rest of the molecule to a radical group, such as having from
one to twelve carbon
atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene,
and the like. Unless
stated otherwise specifically in the specification, an alkylene chain is
optionally substituted as
described for alkyl groups herein.
102691 "Aryl" refers to a radical derived from an aromatic monocyclic or
multicyclic hydrocarbon
ring system by removing a hydrogen atom from a ring carbon atom. The aromatic
monocyclic or
multicyclic hydrocarbon ring system can contain hydrogen and carbon from five
to eighteen
carbon atoms, where at least one of the rings in the ring system is fully
unsaturated, i.e., it contains
a cyclic, delocalized (4n+2) 7c¨electron system in accordance with the Mickel
theory. The ring
system from which aryl groups are derived include, but are not limited to,
groups such as benzene,
fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise
specifically in the
specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is
meant to include aryl
radicals optionally substituted by one or more substituents independently
selected from alkyl,
alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted
aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted
carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl,
optionally substituted heterocyclyl alkyl, optionally substituted heteroaryl,
optionally substituted
heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-0Ra, -Rb-OC(0)-N(Ra)2, -
Rb_N(Ra.)27 _Rb_
C(0)W, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-
N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -1e-S(0)tR0 (where t is 1
or 2), -R3-S(0)tOlta
(where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each W is
independently
-58-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,
methoxy, or
trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heterocyclyl
(optionally substituted with halogen, hydroxy, m ethoxy, or trifluorom ethyl),
h eterocy cl yl al kyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), h
eteroaryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
each Rb is
independently a direct bond or a straight or branched alkylene or alkenylene
chain, and Re is a
straight or branched alkylene or alkenylene chain, and where each of the above
substituents is
unsubstituted unless otherwise indicated.
102701 "Aralkyl- or -aryl-alkyl- refers to a radical of the formula -Re-aryl
where Re is an alkylene
chain as defined above, for example, methylene, ethylene, and the like. The
alkylene chain part
of the aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl
part of the aralkyl radical is optionally substituted as described above for
an aryl group.
102711 "Carbocycly1" or "cycloalkyl" refers to a stable non-aromatic
monocyclic or polycyclic
hydrocarbon radical consisting solely of carbon and hydrogen atoms, which
includes fused or
bridged ring systems, having from three to fifteen carbon atoms. In certain
embodiments, a
carbocyclyl comprises three to ten carbon atoms. In other embodiments, a
carbocyclyl comprises
five to seven carbon atoms. The carbocyclyl is attached to the rest of the
molecule by a single
bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bond
(e.g., no double or
triple bonds between two carbon atoms)) or unsaturated (i.e., containing one
or more double bonds
or triple bonds). Examples of saturated cycloalkyls include, e.g.,
cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated
carbocyclyl is also referred
to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g.,
cyclopentenyl,
cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for
example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,
decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated
specifically in the
specification, the term "carbocyclyl" is meant to include carbocyclyl radicals
that are optionally
substituted by one or more substituents independently selected from alkyl,
alkenyl, alkynyl, halo,
fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted
-59-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted
heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -R
b_N(Ra)2, _Rb_
C(0)10, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-W-C(0)N(Ra)2, -Rb-N(10)C(0)01V, -Rb-
N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1
or 2), -Rb-S(0)tOlta
(where t is 1 or 2) and -Rb-S(0)tN(W)2 (where t is 1 or 2), where each It'd
is independently
hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,
methoxy, or
trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl),
aral kyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), h eterocy cl yl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
each Rb is
independently a direct bond or a straight or branched alkylene or alkenylene
chain, and RC is a
straight or branched alkylene or alkenylene chain, and where each of the above
substituents is
unsubstituted unless otherwise indicated.
[0272] "Carboxylic acid," "COOH," or "(C=0)0H" refers to a radical of the
formula ¨COOH.
Each recitation of -carboxylic acid," -COOH," or -(C=0)0H" provided herein,
unless otherwise
stated, includes a specific and explicit recitation of an esterified
"carboxylic acid," "COOH," or
"(C=0)0H" group (e.g., or radical thereof) In some embodiments, the esterified
carboxylic acid
group (or radical thereof) is (C=0)0-Ci-C4alkyl, wherein alkyl is as defined
hereinabove. In some
embodiments, "carboxylic acid," "COOH," or "(C=0)0H" is COOH. In some
embodiments,
"carboxylic acid," "COOH," or "(C=0)0H" is (C=0)0-Ci-C4alkyl.
[0273] "Carbocyclylalkyl- refers to a radical of the formula ¨Rc-carbocycly1
where RC is an
alkylene chain as defined above. The alkylene chain and the carbocyclyl
radical is optionally
substituted as defined above.
[0274] "Carbocyclylalkenyl- refers to a radical of the formula ¨Rc-carbocycly1
where RC is an
alkenylene chain as defined above. The alkenylene chain and the carbocyclyl
radical is optionally
substituted as defined above.
-60-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
102751 "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom
of the formula ¨
0-Rc-carbocyclyl where RC is an alkylene chain as defined above. The alkylene
chain and the
carbocyclyl radical is optionally substituted as defined above.
102761 -Halo" or -halogen" refers to fluoro, bromo, chloro, or iodo
substituents.
102771 "Haloalkyl" refers to an alkyl radical, as defined above, that is
substituted by one or more
halogen radicals, as defined above, for example, trihalomethyl, dihalomethyl,
halomethyl, and the
like. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for
example, trifluoromethyl,
difluoromethyl, flu oromethyl, 2,2,2-trifluoroethyl, 1-fluoromethy1-2-
fluoroethyl, and the like. In
some embodiments, the alkyl part of the fluoroalkyl radical is optionally
substituted as defined
above for an alkyl group.
102781 The term "heteroalkyl" refers to an alkyl group as defined above in
which one or more
skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the
appropriate number
of substituents or valencies ¨ for example, -CH2- may be replaced with -NH- or
-0-). For example,
each substituted carbon atom is independently substituted with a heteroatom,
such as wherein the
carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable
heteroatom. In some
instances, each substituted carbon atom is independently substituted for an
oxygen, nitrogen (e.g.
-NH-, -N(alkyl)-, or -N(ary1)- or having another substituent contemplated
herein), or sulfur (e.g. -
S-, -S(=0)-, or -S(=0)2-). In some embodiments, a heteroalkyl is attached to
the rest of the
molecule at a carbon atom of the heteroalkyl. In some embodiments, a
heteroalkyl is attached to
the rest of the molecule at a heteroatom of the heteroalkyl. In some
embodiments, a heteroalkyl is
a C1-C18 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12
heteroalkyl. In some
embodiments, a heteroalkyl is a Ci-C6 heteroalkyl. In some embodiments, a
heteroalkyl is a CI-
C4 heteroalkyl. Representative heteroalkyl groups include, but are not limited
to -OCH20Me, or -
CH2CH20Me. In some embodiments, heteroalkyl includes alkoxy, alkoxyalkyl,
alkylamino,
alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and
heterocycloalkylalkyl, as
defined herein. Unless stated otherwise specifically in the specification, a
heteroalkyl group is
optionally substituted as defined above for an alkyl group.
102791 "Heteroalkylene" refers to a divalent heteroalkyl group defined above
which links one part
of the molecule to another part of the molecule. Unless stated specifically
otherwise, a
heteroalkylene is optionally substituted, as defined above for an alkyl group.
102801 "Heterocycly1" refers to a stable 3- to 18-membered non-aromatic ring
radical that
comprises two to twelve carbon atoms and from one to six heteroatoms selected
from nitrogen,
oxygen and sulfur. Unless stated otherwise specifically in the specification,
"heterocycly1" and
-61-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
"heterocycloalkyl" are used interchangeably herein. Unless stated otherwise
specifically in the
specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic
or tetracyclic ring
system, which optionally includes fused or bridged ring systems. The
heteroatoms in the
heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if
present, are optionally
quaternized. The heterocyclyl radical is partially or fully saturated. The
heterocyclyl radical is
saturated (i.e., containing single C-C bonds only) or unsaturated (e.g.,
containing one or more
double bonds or triple bonds in the ring system). In some instances, the
heterocyclyl radical is
saturated (e g , dithiolanyl, dithiolanyl oxide, or dithiolanyl sulfone) In
some instances, the
heterocyclyl radical is saturated and substituted (e.g., dithiolanyl oxide or
dithiolanyl sulfone). In
some instances, the heterocyclyl radical is unsaturated. The heterocyclyl is
attached to the rest of
the molecule through any atom of the ring(s). Examples of such heterocyclyl
radicals include, but
are not limited to, dithiolanyl, dioxolanyl, thienyl[1,3]dithianyl,
decahydroisoquinolyl,
imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl,
piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl,
thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise
specifically in
the specification, the term "heterocyclyl" is meant to include heterocyclyl
radicals as defined
above that are optionally substituted by one or more substituents selected
from alkyl, alkenyl,
alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted
aryl, optionally
substituted aralkyl , optionally substituted aralkenyl , optionally
substituted aralkynyl , optionally
substituted carbocyclyl, optionally substituted carb o cy clyl al kyl,
optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl,
optionally substituted heteroarylalkyl, -Rb-ORa, -1e-OC(0)-Ra, -Rb-OC(0)-0Ra, -
1e-OC(0)-
N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -RID-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-Rc-
C(0)N(Ra)2, -Rb-
N(Ra)C(0)01ta, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-
S(0)tRa (where t is
1 or 2), -Rb-S(0)tOR1 (where t is 1 or 2) and -Rb-S(0)tN(R1)2 (where t is 1 or
2), where each Ra is
independently hydrogen, alkyl (optionally substituted with halogen, hydroxy,
methoxy, or
trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with
halogen, hydroxy, methoxy,
or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heterocyclyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl
-62-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
each RI" is
independently a direct bond or a straight or branched alkylene or alkenylene
chain, and R` is a
straight or branched alkylene or alkenylene chain, and where each of the above
substituents is
un sub stituted unless otherwise indicated.
[0281] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl
radical as defined
above containing at least one nitrogen and where the point of attachment of
the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in the
heterocyclyl radical. An
N-heterocyclyl radical is optionally substituted as described above for
heterocyclyl radicals.
Examples of such N-heterocyclyl radicals include, but are not limited to, 1-
morpholinyl, 1-
piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and
imidazolidinyl.
[0282] "C-heterocyclyl- or "C-attached heterocyclyl" refers to a heterocyclyl
radical as defined
above containing at least one heteroatom and where the point of attachment of
the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A
C-heterocyclyl radical is optionally substituted as described above for
heterocyclyl radicals.
Examples of such C-heterocyclyl radicals include, but are not limited to, 2-
morpholinyl, 2- or 3-
or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
[0283] "Heterocyclylalkyl" refers to a radical of the formula ¨W-heterocycly1
where RC is an
alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the
heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
The alkylene chain of
the heterocyclylalkyl radical is optionally substituted as defined above for
an alkylene chain. The
heterocyclyl part of the heterocyclylalkyl radical is optionally substituted
as defined above for a
heterocyclyl group.
[0284] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom
of the formula ¨
0-R'-heterocyclyl where RC is an alkylene chain as defined above. If the
heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to
the alkyl radical at the
nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is
optionally substituted as
defined above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkoxy radical is
optionally substituted as defined above for a heterocyclyl group.
[0285] "Heteroaryl" refers to a radical derived from a 3- to 18-membered
aromatic ring radical
that comprises two to seventeen carbon atoms and from one to six heteroatoms
selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a
monocyclic, bicyclic,
-63-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
tricyclic or tetracyclic ring system, wherein at least one of the rings in the
ring system is fully
unsaturated, i.e., it contains a cyclic, delocalized (4n+2) 7c¨electron system
in accordance with the
Htickel theory. Heteroaryl includes fused or bridged ring systems. The
heteroatom(s) in the
heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if
present, are optionally
quaternized. The heteroaryl is attached to the rest of the molecule through
any atom of the ring(s).
Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl,
benzindolyl, 1,3 -benzodioxolyl, benzofuranyl,
benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-
benzodioxanyl,
benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl,
benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-
a]pyridinyl, carbazolyl,
cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-
d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-
benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl,
furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9, 1 0-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,1 0-hexahydrocycl oocta[d]pyri dazinyl ,
5,6,7,8,9,1 0-hexahydrocycl oocta[d]pyri di nyl ,
isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl,
indolinyl, isoindolinyl,
isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-
tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl,
oxazolyl, oxiranyl,
5,6,6a,7,8,9, 1 0, 1 0a-octahydrobenzo[h]quinazolinyl, 1-
phenyl-1H-pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,
pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-
d]pyrimidinyl,
pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,
quinolinyl,
isoquinolinyl, tetrahydroquinolinyl,
5,6,7, 8-tetrahy droquinazolinyl,
5,6,7, 8-tetrahydrob enzo[4, 5 ]thieno[2,3 -d]pyrimidinyl,
6,7,8,9-tetrahy dro-5H-cy cl ohepta[4,5 ]thi eno [2,3 -d] pyrimi dinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and
thiophenyl (i.e.
thienyl). Unless stated otherwise specifically in the specification, the term
"heteroaryl" is meant
to include heteroaryl radicals as defined above which are optionally
substituted by one or more
substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,
haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally
substituted aralkenyl , optionally substituted aralkynyl , optionally
substituted carb ocy cl yl ,
-64-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl,
optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, -Rb-
OW, -R"-OC(0)-W, -Rb-OC(0)-0Ra, -Rb-OC(0)-N(W)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-
C(0)0W,
-Rb-C(0)N(10)2, -Rh-O-W-C(0)N(10)2, -Rb-N(10)C(0)0Ra, -Rb-N(10)C(0)1e, -Rb-
N(Ra)S(0)Ita
(where t is 1 or 2), -Rh-S(0)R' (where t is 1 or 2), -Rb-S(0)ORa (where t is 1
or 2) and -Rb-
S(0)N(W)2 (where t is 1 or 2), where each W is independently hydrogen, alkyl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroal kyl
, cycl oal kyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
cycloalkylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl
(optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), h eterocy cl yl
(optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally
substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally
substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond
or a straight or
branched alkylene or alkenylene chain, and It' is a straight or branched
alkylene or alkenylene
chain, and where each of the above substituents is unsubstituted unless
otherwise indicated.
102861 "N-heteroaryl" refers to a heteroaryl radical as defined above
containing at least one
nitrogen and where the point of attachment of the heteroaryl radical to the
rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is
optionally substituted
as described above for heteroaryl radicals
102871 "C-heteroaryl" refers to a heteroaryl radical as defined above and
where the point of
attachment of the heteroaryl radical to the rest of the molecule is through a
carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally substituted as
described above for
heteroaryl radicals.
102881 "Heteroarylalkyl- refers to a radical of the formula ¨W-heteroaryl,
where It' is an alkylene
chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl,
the heteroaryl is
optionally attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the
heteroarylalkyl radical is optionally substituted as defined above for an
alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally substituted as
defined above for a
heteroaryl group.
102891 "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of
the formula ¨0-
W-heteroaryl, where W is an alkylene chain as defined above. If the heteroaryl
is a
-65-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the
alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is
optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is
optionally substituted as defined above for a heteroaryl group.
102901 The compounds disclosed herein, in some embodiments, contain one or
more asymmetric
centers and thus give rise to enantiomers, di astereom ers, and other
stereoisomeric forms that are
defined, in terms of absolute stereochemistry, as (R)- or (S)- Unless stated
otherwise, it is intended
that all stereoisomeric forms of the compounds disclosed herein are
contemplated by this
disclosure. When the compounds described herein contain alkene double bonds,
and unless
specified otherwise, it is intended that this disclosure includes both E and Z
geometric isomers
(e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic
and optically pure
forms, and all tautomeric forms are also intended to be included. The term
"geometric isomer"
refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double
bond. The term
"positional isomer" refers to structural isomers around a central ring, such
as ortho-, meta-, and
para- isomers around a benzene ring.
102911 In general, optionally substituted groups are each independently
substituted or
unsubstituted. Each recitation of an optionally substituted group provided
herein, unless otherwise
stated, includes an independent and explicit recitation of both an
unsubstituted group and a
substituted group (e.g., substituted in certain embodiments, and unsubstituted
in certain other
embodiments). Unless otherwise stated, substituted groups may be substituted
by one or more of
the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, -OR', -
SR', -0C(0)-W, -N(Ra)2, -c(o)R', -C(0)0Ra, -C(0)N(R52, -N(Ra)C(0)0Ra, -0C(0)-
N(Ra)2, -
N(Ra)C(0)Ra, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0)tOlta (where t is 1 or
2), -S(0)tRa (where t
is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently
hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl,
carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
-66-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
102921 "Pharmaceutically acceptable salt" includes both acid and base addition
salts. A
pharmaceutically acceptable salt of any one of the pharmacological agents
described herein is
intended to encompass any and all pharmaceutically suitable salt forms.
Exemplary
pharmaceutically acceptable salts of the compounds described herein are
pharmaceutically
acceptable acid addition salts and pharmaceutically acceptable base addition
salts.
102931 "Pharmaceutically acceptable acid addition salt" refers to those salts
which retain the
biological effectiveness and properties of the free bases, which are not
biologically or otherwise
undesirable, and which are formed with inorganic acids such as hydrochloric
acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,
hydrofluoric acid, phosphorous
acid, and the like. Also included are salts that are formed with organic acids
such as aliphatic mono-
and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic
acids, alkanedioic acids,
aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for
example, acetic acid,
trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic
acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the
like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates,
sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates,
chlorides, bromides, iodides, acetates, trifluoroacetates, propionates,
caprylates, isobutyrates, oxalates,
malonates, succinate suberates, sebacates, fumarates, maleates, mandelates,
benzoates,
chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates,
benzenesulfonates,
toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like.
Also contemplated are salts of amino acids, such as arginates, gluconates, and
galacturonates (see, for
example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical
Science, 66:1-19
(1997)). Acid addition salts of basic compounds are, in some embodiments,
prepared by contacting the
free base forms with a sufficient amount of the desired acid to produce the
salt according to methods and
techniques with which a skilled artisan is familiar.
102941 "Pharmaceutically acceptable base addition salt" refers to those salts
that retain the
biological effectiveness and properties of the free acids, which are not
biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic base or an
organic base to the
free acid. Pharmaceutically acceptable base addition salts are, in some
embodiments, formed with
metals or amines, such as alkali and alkaline earth metals or organic amines.
Salts derived from
inorganic bases include, but are not limited to, sodium, potassium, lithium,
ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts
derived from
-67-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
organic bases include, but are not limited to, salts of primary, secondary,
and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines and basic ion
exchange resins, for example, isopropylamine, trimethylamine, diethylamine,
triethylamine,
tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-
diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-
dibenzylethylenediamine,
chl oroprocaine, hydrab am ine, choline, betai ne, ethyl en edi amine, ethyl
en edi anili n e, N-
methylglucamine, glucosamine, methyl glucamine, theobromine, purines,
piperazine, pi pen i dine,
N-ethylpiperidine, polyamine resins and the like See Berge et a!, ,cupra
Compositions
102951 The meibomian glands are large sebaceous glands located in the eyelids,
and unlike skin,
are unassociated with hair. The meibomian glands produce the lipid layer of
the tear film that
protects it against evaporation of the aqueous phase. The meibomian gland
orifice is located on
the epithelial side of the lid margin, and can be a few hundred microns from
the mucosal side. The
glands are located on both upper and lower eyelids, with higher amounts of the
glands on the
upper eyelid. A single meibomian gland is composed of clusters of secretory
acini that are
arranged circularly around a long central duct and connected to it by short
ductules. The terminal
part of the central duct is lined by an ingrowth of the epidermis that covers
the free lid margin and
forms a short excretory duct that opens as an orifice at the posterior part of
the lid margin just
anterior to the mucocutaneous junction near the inner lid border. The oily
secretion composed of
lipids is synthesized within the secretory acini. The lipid secretion is a
liquid at near body
temperature and is delivered to the skin of the lid margin as a clear fluid,
called "meibum." It
forms shallow reservoirs on the upper and lower lid margins, and consists of a
complex mixture
of cholesterol, wax, cholesteryl esters, phospholipids, with small amounts of
triglycerides,
triacylglycerols, and hydrocarbons. The separate meibomian glands are arranged
in parallel, and
in a single row throughout the length of the tarsal plates in the upper and
lower lids. The extent of
the glands corresponds roughly to the dimensions of the tarsal plates.
102961 The term "keratinized obstruction" as used herein refers to a blockage
of the meibomian
gland, regardless of the location of the blockage. In some embodiments, the
blockage is complete,
whereas in other embodiments, the blockage is partial. Regardless of the
degree of blockage, such
keratinized obstruction leads to meibomian gland dysfunction. In some
embodiments, the
keratinized obstruction is composed of keratinized material and lipids. In
some embodiments, the
keratinized obstruction is a blockage at the meibomian gland orifice and
excretory duct. In some
embodiments, the keratinized obstruction is caused by keratinization of the
epithelium at the lid
-68-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
margin and meibomian gland. In certain instances, the keratin obstruction is
influenced by the
migration or aberrant differentiation of stem cells. In some embodiments, the
keratinized
obstruction results in reduced delivery of oil to the lid margin and tear
film, and stasis inside the
meibomian gland that causes increased pressure, resultant dilation, acinar
atrophy, and low
secretion. In certain instances, keratinization of the meibomian gland causes
degenerative gland
dilation and atrophy.
102971 Ocular surface diseases is a group of diseases including, but not
limited to, dry eye
syndrome (including evaporative DES and/or aqueous deficiency DES),
blepharitis, keratitis,
meibomian gland dysfunction, conjunctivitis, lacrimal gland disorder, contact
lens related
conditions and inflammatory, infectious, or autoimmune diseases or disorders
of the anterior
surface of the eye. The term, "meibomian gland dysfunction," as used herein,
refers to chronic,
diffuse abnormality of the meibomian glands, that is characterized by terminal
duct obstruction or
qualitative or quantitative changes in the glandular secretion, or both. MGD
may result in
alteration of the tear film, eye irritation symptoms, inflammation, or ocular
surface disease. The
most prominent aspects of MGD are obstruction of the meibomian gland orifices
and terminal
ducts and changes in the meibomian gland secretions.
102981 In some instances, meibomian gland dysfunction (MGD) is a chronic,
diffuse abnormality
of the meibomian glands, which can be characterized by terminal duct
obstruction and/or
qualitative/quantitative changes in the glandular secretion. Terminal duct
obstruction is caused
by hyperkeratinization of the ductal epithelium (Nichols et al, Inv. Oph. &
Vis. Sci. (2011);
52(4):1922-1929). These alterations in both meibum quality and expression may
result in
alteration of the tear film, symptoms of eye irritation, and ocular surface
disease such as
evaporative dry eye. The principal clinical consequence of MGD is evaporative
dry eye syndrome
and large population based studies (i.e., Bankok Study and the Shihpai Eye
Study) estimate that
over 60% of patients with dry eye symptoms also have MGD (Schaumberg et al,
Investigative
Ophthalmology and Visual Science. (2011); 52(4):1994-2005).
102991 MGD is a leading contributor of dry eye syndrome. The occurrence of dry
eye syndrome
is widespread and affects about 20 million patients in the United States
alone. Dry eye syndrome
is a disorder of the ocular surface resulting from either inadequate tear
production or excessive
evaporation of moisture from the surface of the eye. Tears are important to
corneal health because
the cornea does not contain blood vessels, and relies on tears to supply
oxygen and nutrients. Tears
and the tear film are composed of lipids, water, and mucus, and disruption of
any of these can
-69-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
cause dry eye. An inadequate amount of lipids flowing from the meibomian
glands as caused by
a keratinized obstruction, may cause excessive evaporation, thereby causing
dry eye syndrome.
[0300] In some embodiments, altered meibomian gland secretion is detected by
physically
expressing the meibomian glands by applying digital pressure to the tarsal
plates. In subjects
without MGD, the meibum is a pool of clear oil. In MGD, both the quality and
expressibility of
the expressed material is altered. The altered meibum is also known as
meibomian excreta and is
made up of a mixture of altered secretions and keratinized epithelial
material. In MGD, the quality
of expressed lipid varies in appearance from a clear fluid, to a viscous fluid
containing particulate
matter and densely opaque, toothpaste-like material. The meibomian orifices
may exhibit
elevations above surface level of the lid, which is referred to as plugging or
pouting, and is due to
obstruction of the terminal ducts and extrusion of a mixture of meibomian
lipid and keratinized
material.
[0301] Obstructive MGD is characterized by all or some of the following: 1)
chronic ocular
discomfort, 2) anatomic abnormalities around the meibomian gland orifice
(which is one or more
of the following: vascular engorgement, anterior or posterior displacement of
the mucocutaneous
junction, irregularity of the lid margin) and 3) obstruction of the meibomian
glands (obstructive
findings of the gland orifices by slit lamp biomicroscopy (pouting, plugging
or ridge), decreased
meibum expression by moderate digital pressure).
[0302] Current methods for assessing and monitoring MGD symptoms include, but
are not limited
to patient questionnaires, meibomian gland expression, tear stability break up
time, and
determining the number of patent glands as seen by digital expression.
[0303] In some embodiments, the symptoms of a patient are assessed by asking
the patient a series
of questions. Questionnaires allow the assessment of a range of symptoms
associated with ocular
discomfort. In some embodiments, the questionnaire is the SPEED questionnaire.
The SPEED
questionnaire assesses frequency and severity of a patient's dry eye symptoms.
It examines the
occurrence of symptoms on the current day, past 72 hours and past three
months. A SPEED score
is tallied based on the patient's answers to the questions, to give a range of
severity of the patient's
symptoms. The SPEED questionnaire includes questions such as the following: 1)
what dry eye
symptoms are you experiencing, and when do they occur? 2) how frequently do
you experience
dryness, grittiness, or scratchiness in your eyes? 3) how often do you
experience soreness or
irritation of the eyes? 4) how often do you experience burning or watering of
the eyes? 5) how
often do you experience eye fatigue? and 6) how severe are the symptoms?
-70-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
103041 Meibomian gland expressibility is optionally determined to assess the
meibomian gland
function. In normal patients, meibum is a clear to light yellow oil. Meibum is
excreted from the
glands when digital pressure is placed on the glands. Changes in meibomian
gland expressibility
are one potential indicator of MGD. In some embodiments, during expression,
quantifying the
amount of physical force applied during expression is monitored in addition to
assessing lipid
volume and lipid quantity.
103051 Tear stability break up time (TBUT) is a surrogate marker for tear
stability. Tear film
instability is a core mechanism in dry eye and MGD Low TBUT implies a
possibility of lipid
layer compromise and MGD. TBUT is optionally measured by examining fluorescein
breakup
time, as defined as the time to initial breakup of the tear film after a
blink. Fluorescein is optionally
applied by wetting a commercially available fluorescein-impregnated strip with
saline, and
applied to the inferior fornix or bulbar conjuctiva. The patient is then asked
to blink several times
and move the eyes. The break up is then analyzed with a slit lamp, a cobalt
blue filter, and a beam
width of 4 mm. The patient is instructed to blink, and the time from upstroke
of the last blink to
the first tear film break or dry spot formation is recorded as a measurement.
103061 Other methods for assessing MGD symptoms, include but are not limited
to, Schirmer test,
ocular surface staining, lid morphology analysis, meibography, meibometry,
interferometry,
evaporimetry, tear lipid composition analysis, fluorophotometry, mei scometry,
osmolarity
analysis, indices of tear film dynamics, evaporation and tear turnover.
103071 Current treatments for MGD include lid warming, lid massage, lid
hygiene, lid expression
and meibomian gland probing. Pharmacological methods, prior to those described
herein, have
not been used.
103081 Lid hygiene is considered the primary treatment for MGD and consists of
three
components: 1) application of heat, 2) mechanical massage of eyelids and 3)
cleansing the eyelid.
Eyelid warming procedures improve meibomian gland secretion by melting the
pathologically
altered meibomian lipids. Warming is achieved by warm compresses or devices.
Mechanical lid
hygiene includes the use of scrubs, mechanical expression and cleansing with
various solutions of
the eyelashes and lid margins. Lid margins are optionally also cleansed with
hypoallergenic bar
soap, dilute infant shampoo or commercial lid scrubs. Physical expression of
meibomian glands
is performed in a physician's office or is performed by the patient at home.
The technique varies
from gentle massage of the lids against the eyeball to forceful squeezing of
the lids either against
each other or between a rigid object on the inner lid surface and a finger,
thumb, or rigid object
(such as a glass rod, cotton swab, or metal paddle) on the outer lid surface.
The rigid object on the
-71-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
inner lid surface protects the eyeball from forces transferred through the
eyelid during expression
and to offer a stable resistance, to increase the amount of force that is
applied to the glands.
103091 Eyelid warming is limited because the warming melts the lipids, but
does not address
movement of the keratinized material. Further, eyelid warming induces
transient visual
degradation due to corneal distortion. Mechanical lid hygiene is also limited
because the force
needed to remove an obstruction can be significant, resulting in significant
pain to the patient. The
effectiveness of mechanical lid hygiene is limited by the patient's ability to
tolerate the associated
pain during the procedure Other treatments for MGD are limited
103101 Physical opening of meibomian glands obstruction by meibomian gland
expression is an
acceptable method to improve meibomian gland secretion and dry eye symptoms.
In addition
probing of the meibomian gland canal has been used to open the obstructed
canal. Both methods,
expression and probing, are limited, however, by the pain induced by the
procedure, the possible
physical insult to the gland and canal structures and their short lived effect
estimated at days and
weeks. Therefore, methods are needed to improve patient comfort, which will
not cause harm to
the meibomian glands and canals, that will reduce the dependency on frequent
office visits and
improve secretion of meibum.
103111 Patent US 9,463,201 entitled, "Compositions and methods for the
treatment of meibomian
gland dysfunction" describes a method for treating meibomian gland dysfunction
involving the
topical administration of a therapeutically-effective amount of at least one
keratolytic agent in an
ophthalmically-acceptable carrier. The patent includes keratolytic agents that
are inorganic
selenium (Se) compounds such as selenium disulfide (SeS2) or organoselenium
compounds such
as Ebselen (2-Phenyl-1,2-benzoselenazol-3-one). This agent would treat the
underlying cause of
MGD, but not a "plus" inflammatory disease as described by the DEWS report on
MGD.
103121 The role of inflammation in the etiology of MGD is controversial. The
terms posterior
blepharitis and MGD are not synonymous. Posterior blepharitis describes
inflammatory conditions
of the posterior lid margin and has various causes, of which MGD can be one
possible cause
(Nichols et al 2011). In its earliest stages, MGD is not associated with
clinical signs characteristic
of posterior blepharitis. As MGD progresses, an MGD-related posterior
blepharitis is said to be
present. MGD-related posterior blepharitis affects the meibomian glands and
meibomian gland
orifices. MGD-related posterior blepharitis is characterized by flora changes,
esterase and lipase
release, lipid changes, and eyelid inflammation. Hyperkeratinization of the
meibomian gland
epithelium (thickening of the lining of the glands) may lead to obstruction
and a decrease in the
quantity of meibomian gland secretions and may be responsible for MGD-related
posterior
-72-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
blepharitis. Diagnosis of MGD-related posterior blepharitis includes meibomian
gland expression
with demonstration of an altered quality of expressed secretions, and/or by a
loss of gland
functionality (decreased or absent expressibility). The TFOS report on
Meibomian Gland Disease
specifically notes that anterior blepharitis and exacerbated inflammatory
ocular surface disease
are "plus" diseases to MGD which are managed by topical, ocular steroids
(Nichols et al 2011).
Since these "plus" conditions can be present in various levels of severity
from early to late MGD
there is a need for treatments and/or combinations of treatments that can
target both the underlying
non-inflammatory pathophysiology of MGD and inflammation associated with these
comorbid
conditions.
103131 MGD-related inflammatory eye disease may comprise a different mechanism
than
blepharitis-related MGD. MGD-related inflammatory eye disease is characterized
by an
inflammatory cascade involving activation and migration of T lymphocytes to
the inflamed tissue.
T lymphocyte infiltration may result in lacrimal gland stimulation and
upregulation of cytokines.
Exemplary cytokines that may be involved in MGD-related inflammatory eye
disease include, but
are not limited to, interleukin-1, interleukin-4, interleukin-6, inteleukin-8,
interferon gamma,
macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha.
Kinase pathways
including the mitogen activated protein kinase (MAPK) pathway are also
activated in the
inflammatory cascade. The inflammatory process results in loss of mucin-
producing goblet cells
and destruction of the ocular surface that can lead to further damage.
103141 Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is
considered a self-
sustaining disease that is progressively disconnected from its initial cause.
Dry eye syndrome is
associated with inflammation at the ocular surface and periocular tissue.
Inflammation is
characterized by the activation and migration of T lymphocytes to the inflamed
tissue including
in the conjunctiva and lacrimal glands. Inflammatory cytokines, chemokines,
and matrix
metalloproteinase have also been identified as being increased.
103151 Animal models of dry eye disease have been established and reviewed
(Barabino, et al,
(Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)). Barabino, et al, (Invest.
Ophthalmol. Vis.
Sci. 2005, 46:2766-2771) described a model wherein exposure of normal mice to
a low-humidity
environment in a controlled-environment chamber leads to significant
alterations in tear secretion,
goblet cell density, and acquisition of dry eye-related ocular surface signs.
However, no single
animal model adequately accounts for the immune, endocrine, neuronal and
environmental factors
which contribute to dry eye pathogenesis.
-73-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
10M61 Anti-inflammatory agents may be used to treat ocular surface diseases or
disorders
including dry eye syndrome. Corticosteroids are an effective anti-inflammatory
therapy in dry eye
disease. For example, in a 4-week, double-masked, randomized study in 64
patients with dry eye
and delayed tear clearance, loteprednol etabonate 0.5% ophthalmic suspension
(Lotemax [Bausch
and Lomb, Rochester, NY]), QID, was found to be more effective than its
vehicle in improving
some signs and symptoms (Pflugfelder et al, Am J Ophthalmol (2004); 138:444-
57). The TFOS
2007 report on dry eye disease went so far as to conclude that, "In the US
Federal Regulations,
ocular corticosteroids receiving "class labeling" are indicated for the
treatment " of steroid
responsive inflammatory conditions of the palpebral and bulbar conjunctiva,
cornea and anterior
segment of the globe such as allergic conjunctivitis, acne rosacea,
superficial punctate keratitis,
herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis,
when the inherent hazard
of steroid use is accepted to obtain an advisable diminution in edema and
inflammation.- KCS, in
some instances, is included in this list of steroid-responsive inflammatory
conditions (Therapy
Subcommittee of the International Dry Eye WorkShop, 2007. Management and
Therapy of Dry
Eye Disease: Report of the Management and Therapy Subcommittee of the
International Dry Eye
WorkShop (2007). 2007;5: 163-178)." While the US FDA does not agree with this
conclusion,
short courses of steroids, especially Lotemax, are which can be used to treat
inflammation
associated with dry eye disease.
[0317] Other anti-inflammatory agents include nonsteroidal anti-inflammatory
drugs (NSAlDs).
NSA1Ds inhibit the activity of cyclooxygenases including cyclooxygenase-1 (COX-
1) and
cyclooxygenase-2 (COX-2), which are enzymes involved in the synthesis of
prostaglandins and
thromboxanes from arachidonic acid. Prostaglandin and thromboxane signaling
are involved in
inflammation and immune modulation. In some cases, NSAIDs are used for
treating dry eye
disease by treating the inflammation at the ocular surface.
103181 Treatment of dry eye is also accomplished through agents that enhance
tear fluid and
mucin production. For example, agonists of the P2Y2 receptor have been shown
to increase tear
fluid and mucin secretion. The mechanism is thought to involve P2Y2 signaling
to raise
intracellular calcium and open chloride channels in the apical membrane. The
P2Y2 receptor
belongs to the family of purinergic receptors, which have been classified into
P1 receptors and P2
receptors on the basis of their native agonism by purine nucleosides and
purine and pyrimidine
nucleotides, respectively. P2 receptors are further distinguished
physiologically into two types:
P2X receptors and P2Y receptors. The P2Y receptors are involved in diver
signaling including
platelet aggregation, immunity, lipid metabolism, and bone activity. Several
studies have also
-74-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
demonstrated the presence of P2X and P2Y receptors in ocular tissues,
including the retina, ciliary
body, and lens. These studies indicate that P2Y2 receptors appear to be the
main subtype of
purinergic receptor located at the ocular surface. P2Y2 receptors have also
been demonstrated to
be localized in ocular tissues in the conjunctival epithelial goblet and
serous cells and meibomian
gland acinus and ductal epithelial cells of the rhesus macaque.
Lifitegrast
103191 The chemical name for lifitegrast can be (S)-2-(2-(benzofuran-6-
carbony1)-5,7-dichloro-
1,2,3 ,4-tetrahydroi soqu inoline-6-carb oxamid o)-3 -(3 -(methyl
sulfonyl)phenyl)propanoic acid
Lifitegrast has a molecular formula of C29H24C12N207S and a molecular weight
is about 615.5
g/mol. Lifitegrast can be administered as a 5% ophthalmic solution with a pH
of 7.0-8.0 and an
osmol al i ty range of 200-330 m 0 sm ol /kg. The structural formula of
lifitegrast is:
H 0 CI
0"0 HO
0
CI 0
0
(S)-2-(2-(benzofuran-6-carbonyI)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-
carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoic acid
103201 Lifitegrast is indicated for the treatment of the signs and symptoms of
dry eye disease
(DED). Lifitegrast binds to the integrin lymphocyte function-associated
antigen-1 (LFA-1), a cell
surface protein found on leukocytes and blocks the interaction of LFA-1 with
its cognate ligand
intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in
corneal and
conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can
contribute to the formation
of an immunological synapse resulting in T-cell activation and migration to
target tissues. In vitro
studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in
a human T-cell line
and may inhibit secretion of inflammatory cytokines in human peripheral blood
mononuclear
cells. The exact mechanism of action of lifitegrast in dry eye disease is not
known. More
information about lifitegrast can be found, for example, in the following US
patents: 10,124,000,
7,314,938, 7,745,460, 7,790,743, 7,928,122, 8,084,047, 8,168,655, 8,367,701,
8,592,450,
8,927,574, 9,085,553, 9,216,174, 9,353,088, 9,447,077, and 9,890,141.
103211 Described herein are compounds (e.g., keratolytic conjugates and/or
dual acting-agents)
which address simultaneously the non-inflammatory keratolytic blockage
component of
meibomian gland dysfunction and the inflammation associated dry eye disease
including aqueous
deficiency. In some embodiments, a compound provided herein is useful as
either an acute therapy
-75-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
(e.g., by a trained specialist or physician) or as a chronic therapy (e.g., in
the hands of a patient,
or alternatively, by a trained specialist or physician). A compound provided
herein is tested, in
some embodiments, using the assays and methods described herein (e.g., as
described in the
examples). In some embodiments, a compound provided herein represents a
significant advance
in the art as the first-order metabolites obtained from metabolism of the
agents are operative
against both the keratolytic and the inflammatory component of dry eye
disease.
103221 In some embodiments, provided herein is a compound, having the
structure of Formula
R12 0 R2
(R13),-,
0 R1
R4
R3 0
Formula (I)
wherein:
R4- is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,
cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted;
R2, le, and R4 are each independently H, cyano, halo, ester, alkoxy, alkyl,
heteroalkyl,
cycloalkyl or heterocyclyl, wherein the alkoxy, alkyl, heteroalkyl, cycloalkyl
or heterocyclyl is optionally substituted;
Rt2 is _La_R12a, wherein La is a bond, alkyl, or heteroalkyl, and R12 is
absent, a
cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, wherein the
cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is optionally substituted;
each RH is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,
cycloalkyl or
haloalkyl;
n is 0-6; and
RQ is -La-D, wherein:
D is a keratolytic agent; and
L' is a linker,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103231 In some embodiments, L' comprises one or more linker group, each linker
group being
independently selected from the group consisting of a bond, -0-, -S-, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), disulfide, ester, and carbonyl (>C=0). In some embodiments,
the keratolytic
-76-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
agent comprises one or more groups of the group (e.g., keratolytic group, such
as a group
conferring keratolytic activity), each group (e.g., keratolytic group) being
independently selected
from the group consisting of thiol, disulfide, selenium (e.g., selenide,
diselenide), carboxylic acid
or a group which can be metabolized to a carboxylic acid.
103241 In some embodiments, provided herein is a compound having the structure
of Formula (I-
A):
R12 0 R2
(R13)n
RNYyL
0
R4NyR
R3 0
Formula (I-A)
wherein:
It' is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,
cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted;
R2, le, and le are each independently H, cyano, halo, ester, alkoxy, alkyl,
heteroalkyl,
cycloalkyl or, heterocyclyl, wherein the alkoxy, alkyl, heteroalkyl,
cycloalkyl
or, heterocyclyl is optionally substituted;
Ri2 is _La_R12a, wherein Ti' is a bond, alkyl, or heteroalkyl, and R12 is
absent, a
cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, wherein the
cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
each le3 is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,
cycloalkyl, or
haloalkyl;
n is 0-6,
Y is 0 or S; and
RN is alkyl or heteroalkyl substituted with at least one oxo, and further
optionally
substituted,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103251 In some embodiments, provided herein is a compound having the structure
of Formula (T-
B):
-77-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
R120 R2
(R13)n
RNOr1/41
1;4
0 R6
R4
R3o
Formula (I-B)
wherein.
Rl is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,
cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted;
R2, R3, and le are each independently H, cyano, halo, ester, alkoxy, alkyl,
heteroalkyl,
cycloalkyl or, heterocyclyl, wherein the alkoxy, alkyl, heteroalkyl,
cycloalkyl
or, heterocyclyl is optionally substituted;
R12 is _La_R12a, wherein L,a is a bond, alkyl, or heteroalkyl, and R12a is
absent, a
cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, wherein the
cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
each R" is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,
cycloalkyl, or
haloalkyl;
n is 0-6; and
RN is alkyl or heteroalkyl substituted with at least one oxo, and further
optionally
substituted,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103261 In certain embodiments, the compound has the structure of Formula (I-
C):
0=s=0
0 CI
RN 0
0
C I 0
0
Formula (I-C)
or a pharmaceutically acceptable salt thereof
103271 In some embodiments, the alkyl or heteroalkyl of RN is substituted with
one or more
substituent, each substituent independently selected from the group consisting
of alkyl,
-78-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide,
diselenide, sulfone,
amide, halo, oxo, heterocyclyl, and cycloalkyl, wherein the heterocyclyl, and
cycloalkyl is
optionally substituted (e.g., with one or more substituent selected from the
group consisting of
alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, selenide,
diselenide, sulfone,
amide, halo and oxo).
103281 In some embodiments, RN is
X R15 y0
0 Ri4
wherein:
X is -0- or a bond;
RI-4 is hydrogen, alkyl, heteroalkyl, or haloalkyl;
R" is alkyl or heteroalkyl, the alkyl or heteroalkyl being optionally
substituted,
or a pharmaceutically acceptable salt or solvate thereof.
103291 In some embodiments, the alkyl or heteroalkyl of R" is substituted with
one or more
substituent, each substituent independently selected from the group consisting
of alkyl,
heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide,
diselenide, sulfone,
amide, ester, carboxylic acid, halo, oxo, heterocyclyl, and cycloalkyl,
wherein the heterocyclyl,
and cycloalkyl is optionally substituted (e.g., with one or more substituent
selected from the group
consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide,
selenol, sulfone, amide, ester
halo and oxo).
103301 In some embodiments, le is H. In some embodiments, n is 0. In some
embodiments, le is
optionally substituted aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some
embodiments, RI is
heteroaryl. In some embodiments, RI- is benzofuran. In some embodiments, R2
and R4 are each
independently H, halo, alkoxy, or alkyl. In some embodiments, R2 and R4 are
halo. In some
embodiments, R2 and R4 are chloro. In some embodiments, 102 is optionally
substituted aryl,
heteroaryl, aryl-alkyl, or heteroaryl-alkyl. In some embodiments, RI-2 is
optionally substituted
aryl-alkyl. In some embodiments, R12 is substituted aryl-alkyl. In some
embodiments, R12 is a
sulfonyl substituted aryl-alkyl.
103311 Provided in some embodiments herein is a compound having the structure
of Formula
(Ia').
-79-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0=S=0
0 CI
'12-0
0
CI 0
0
Formula (Ia')
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein,
Lz is bond, -(C=0)0(CR8R9)z-, -0(C=0)(OCR8R9),-, or -(C=0)(OCR8R9)z-;
each le and R9 is independently H, halogen, Ci-C3-alkyl, C1-C3-haloalkyl, C1-
C3-
alkoxy, C3-05-cycloalkyl, or le and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
R is substituted (e.g., straight or branched) alkyl, substituted (e.g.,
straight or branched)
heteroalkyl, or substituted heterocycloalkyl (e.g., (N-) substituted with
alkyl (e.g.,
the alkyl being further substituted with oxo and/or thiol)), the substituted
alkyl
being substituted with one or more (alkyl) substituent, at least one (alkyl)
sub stituent being independently selected from the group consisting of -OH, -
SH, -
COOH, substituted or unsubstituted (e.g., unsaturated) cycloalkyl,
dithiolanyl,
dithiolanyl sulfone, and dithiolanyl oxide, or the substituted heteroalkyl
being
substituted with one or more (heteroalkyl) substituent, at least one
(heteroalkyl)
substituent being independently selected from the group consisting of
dithiolanyl,
dithiolanyl sulfone, dithiolanyl oxide, -SH, -COOH, and thioalkyl, the
substituted
alkyl, substituted heteroalkyl, or substituted heterocycloalkyl being further
optionally substituted, and
when R is alkyl substituted with dithiolanyl, Lz is -(C=0)0CH2-, -
(C=0)0CH2CH2-, or -(C=0)0CH2CH2CH2-.
103321 In some embodiments, provided herein is a compound having the structure
of Formula
(Ia):
-80-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0=S=0
CI
'12-0
0
CI 0
0
Formula (Ia)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein,
Lz is bond, -0(C=0)(OCR8R9)z-, or -(C=0)(OCR8R9)z-;
each le and R9 is independently H, halogen, Ci-C3-alkyl, C1-C3-haloalkyl, C1-
C3-
alkoxy, C3-05-cycloalkyl, or le and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6; and
R is substituted (e.g., straight or branched) alkyl, substituted (e.g.,
straight or branched)
heteroalkyl, or substituted heterocycloalkyl (e.g., (N-) substituted with
alkyl
further substituted with oxo and/or thiol), the substituted alkyl being
substituted
with one or more (alkyl) substituent, at least one (alkyl) substituent being
independently selected from the group consisting of -SH, substituted or
unsubstituted (e.g., unsaturated) cycloalkyl, and dithiolanyl oxide, or the
substituted heteroalkyl being substituted with one or more (heteroalkyl)
substituent, at least one (heteroalkyl) substituent being independently
selected from
the group consisting of -SH, -COOH, and thioalkyl, the substituted alkyl,
substituted heteroalkyl, or substituted heterocycloalkyl being further
optionally
substituted.
103331 In some embodiments, Lz is bond. In some embodiments, Lz is -
(C=0)(OCR8R9)z-. In
some embodiments, Lz is -0(C=0)(OCR8R9)z-. In some embodiments, Lz is -
(C=0)0(CR8R9)z-.
In some embodiments z is 1-3. In some embodiments, z is 1. In some
embodiments, each le and
R9 is independently H or C1-C3-alkyl. In some embodiments, each le is H and
each R9 is Ci-C3-
alkyl. In some embodiments, each R8 is H and each R9 is CH3. In some
embodiments, R8 and R9
are H.
-81-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
103341 In some embodiments, Lz is -(C=0)0CH(CH3)-.
103351 In some embodiments, L' is -0(C=0)0CH(CH3)-.
103361 In some embodiments, L' is -(C=0)0CH2-, -(C=0)0CH2CH2-, or -
(C=0)0CH2CH2CH2-
. In some embodiments, L' is -(C=0)0CH2-. In some embodiments, L' is -
(C=0)0CH2CH2-. In
some embodiments, LL is -(C=0)0CELCELCH2-.
103371 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxyl, thiol,
amino, acetamide, -
COOH, substituted unsaturated cycloalkyl (e.g., being substituted with one or
more Ci-C4 alkyl),
unsubstituted heterocycloalkyl (e.g., dithiolanyl),
and substituted heterocycloalkyl (e.g.,
dithiolanyl oxide or dithiolanyl sulfone).
103381 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxy, optionally
substituted alkoxy
(e.g., optionally substituted with oxo and hydroxy or oxo and Ci-C3 alkoxy)),
oxo, optionally
substituted alkyl (e.g., optionally substituted with alkoxy further optionally
substituted with oxo,
Ci-C4 alkyl, and/or hydroxy), optionally substituted heterocycloalkyl (e.g.,
optionally substituted
dioxane (e.g., 1,3 dioxanyl optionally substituted with methyl), dithiolanyl,
or dithiolanyl oxide),
hydroxyalkyl, thiol, acetamide, substituted unsaturated cycloalkyl (e.g.,
being substituted with one
or more Ci-C4 alkyl), and amino.
103391 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of thiol, amino,
acetamide, substituted
unsaturated cycloalkyl (e.g., being substituted with one or more C1-C4 alkyl),
and substituted
heterocycloalkyl (e.g., dithiolanyl oxide).
103401 In some embodiments, L' is -0(C=0)0CH(CH3)- and R is substituted (e.g.,
straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
thiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more C3-C4 alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).
103411 In some embodiments, L' is -(C=0)0CH(CH3)- and R is substituted (e.g.,
straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
-82-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
thiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more C1-C4 alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).
103421 In some embodiments, R is:
0
s H NH 2
NH
H
HO HO\
H S HS
HS
,
o,,,
s
s-s s-
,
oe
s-ts
or
103431 In some embodiments, R is:
0
s H N H2 NH
H S
H S
, or
,
0 e
SiS
Se .
103441 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or more -C-O-C- (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103451 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or more ester, one or more carbonate, one or more
amide, and/or one
or more disulfide (e.g., within the (e.g., linear or branched) heteroalkyl
chain).
103461 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
103471 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one carbonate (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
-83-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
103481 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two ester (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103491 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester (e.g., within the (e.g., linear or branched)
heteroalkyl chain).
103501 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one carbonate (e.g., within the (e.g.,
linear or branched)
heteroalkyl chain).
103511 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two ester and one amide (e.g., within the (e.g.,
linear or branched)
heteroalkyl chain).
103521 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one amide (e.g., within the (e.g., linear
or branched)
heteroalkyl chain).
103531 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103541 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103551 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
103561 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide and one ester (e.g., within the
(e.g., linear or branched)
heteroalkyl chain).
103571 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
103581 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of optionally
substituted Ci-C6 alkyl, acetamide, hydroxy, heterocycloalkyl, thiol,
thioalkyl, amino, and
carboxylic acid.
-84-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
103591 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycl oal kyl substituted with carboxyl i c acid).
103601 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (e.g., N-
attach ed) heterocycl oal kyl (e.g., optionally substituted with carboxyl i c
acid).
103611 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with substituted Ci-Co
alkyl, the Ci-Co alkyl
being substituted with heteroalkyl being further optionally substituted with
one or more
sub stituent, each sub stituent being independently selected from the group
consisting of hydroxy,
carboxylic acid, optionally substituted N-substituted pyrrolidinyl (e.g.,
optionally substituted with
carboxylic acid)).
103621 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with heterocycloalkyl. In
some embodiments, R
is substituted (e.g., linear or branched) heteroalkyl, the (e.g., linear or
branched) heteroalkyl being
substituted with 1 , 2-di th i ol an e, 1 , 2-di th i ol an e oxide,
optionally substituted di ox an e (e.g.,
optionally substituted with one or more
C1-
C6 alkyl), (e.g., N-substituted) pyrrolidine (e.g., substituted with alkyl
further substituted with oxo,
thiol, and C1-C3 alkyl), or substituted (e.g., N-attached) pyrrolidine (e.g.,
substituted with
carboxylic acid).
103631 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with acetamide and
carboxylic acid.
103641 In some embodiments, Lz is -(C=0)0CH(CH3)- and R is substituted (e.g.,
linear or
branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl being
substituted with one or more
substituent, each substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (e.g., N-
attached) heterocycloalkyl (e.g., optionally substituted with carboxylic
acid).
-85-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
103651 In some embodiments, Lz is -0(C=0)0CH(CH3)- and R is substituted (e.g.,
linear or
branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl being
substituted with one or more
(heteroalkyl) substituent, each (heteroalkyl) substituent being independently
selected from the
group consisting of thioalkyl, amino, carboxylic acid, Ci-C6 alkyl, acetamide,
thiol, oxo, and
optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., optionally
substituted with
carboxylic acid).
103661 In some embodiments, R is:
S¨s 0
0
e s
0
o -"SH
o SH
0 0 o "SH
HO)LN N N OH HS KII.N
NH2 0 N H2 0
0
HN 0
H 0y1õ1OH
0 S, HO 0
HN
HN s S N 0
0
0 OH
OH
0
0 tl-D OyHS
NH
-
0 S,s 0 N H2
HO 0
N H2
0
\,,r0
=-"i(NH 0
or .
103671 In some embodiments, R is:
-86-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
SH
o ,,SH
0 0 .' 0
H H 0 ''SH
H0)LN----T N'-"A Sys-'-')L'N"--..y N ----)L-'0H HSN -,--õ, /
H H
NH2 0 , NH2 0 H
OH
0
0
l'\c--D
HO 0,1(1,1
0 S ,s /"\I
0 s,
HO 0 S
HN.õ.,..s,S..õ,..1..õ...,-,..õ.õ/
¨:)1,..itrs,Sõ,..1õ,õ...õ/
.--:,.-
HO 0
Oy-
0
HS,,.,..NH
0 NH2 \,.f..0
NH 0
0 0 H N.,--...s,Si ).1.'
NH
HOS--S-)?, )y 0 0 HS....õ..-1,...4
NH2 H -'-'
,or
f .
103681 In some embodiments, R is substituted branched heteroalkyl.
103691 In some embodiments, R is:
OH
0 0
H N )C 0,11:11-D
HO.õTrH
0 S,
S HO 0
0 S'S
HNs,S7
-b--1-1S'S1
.-..,
HO 0 or
103701 In some embodiments, R-L' is:
-87-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
HN A' ""'"i 0 0
HOyL,1
'.0-"S'S0H
0 0 S,s HN ,Ir
H r
.=,. _..-.,
HO 0 0 , 0 0 OH
,or
OH
0
0 i\--1-D
--,1
HO
00 s
0 S
-NsS 0,,TA
I
0 .
103711 In some embodiments, R-Lz is:
OH
0 0
HOy-1-,1
.,,r.0 0 Sõs 0
S,s
HO
0
HO 0 or 0
.
103721 In some embodiments, R is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
further substituted with oxo and thiol).
103731 In some embodiments, R is:
CD
-----µ _--- N -.1
HS 0 0 or H
103741 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
lipoic acid sulfonyl
-88-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
(Lipsulf), a radical of N-acetyl cysteine (NAC), a radical of cysteine (Cys),
a radical of glutathione
(GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).
103751 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sul foxi de (Li pox), a radical of dihydrolipoic acid (di HLi p), a
radical of N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
103761 In some embodiments, R comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
103771 In some embodiments, R comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
103781 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]-, [Lac-
NAC]., [Cys-Cys]., [difiLip-NAC-NAC]., [difiLip-NAC]., [difiLip-Cap-Cap].,
[diFILip-Cap].,
[difiLip-Cys-Cys]., [diElLip-Cys]., [diElLip-Lipox-Lipox]., and [diHLip-
Lipox]..
103791 Unless stated otherwise, a radical (or.) is molecule having unpaired
electrons. In some
embodiments, the radical is a radical of a heteroatom (e.g., -0., -N., or -
S.). In some embodiments,
the radical (e.g., the molecule having unpaired electron) is paired with
another unpaired electron
of another molecule to form paired electrons. In some embodiments, a radical
of a keratolytic
agent provided herein is paired with any compound provided herein. In some
embodiments, a first
-89-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
radical of a keratolytic agent provided herein is paired with a second radical
of a keratolytic
provided herein.
103801 In some embodiments, the radical of the keratolytic group is the point
of attachment of R
to the rest of the molecule. In some embodiments, (the thiol radical of) R
each independently
attach to the rest of the molecule to form a disulfide bond.
103811 In some embodiments, R is:
HO\
,--,,,,)-% 0 HSHS/L'S HO H0
''''\ /
0 e S--
O
0,o s
s_g -s-s sis
C-",r, C-"--.L-..-,s' C-'-'1"-./' '-... ..-..,5-= t5'
ss' sr sr 0
,
0
SH
0 0
HO)*(`r'ANXir \
Els1 HS ,õ-1-õ, H
NH2 0
,,,,SH C¨J
0 0 N / r SH
H 0
NH2 0 , HS H
0
HN A" 0
HalrHssi--.....-^-,--^-,---S--s-^-...r)L-OH
S
,Sr HN,.ir
H
HO 0 0 OH
-90-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
OH
0
O¨
HO 0 trID
..=Th
0 S,s 0 NH2
....JNs--Ssi HO-j1S--S---11 1
NH2
0 ---
0
NH
NH
HN
--A HS-----
>(s-D ---(sD
......,-,,s,S,...s, N isse N/ S---1 -
,5--,
0 0
---µ0
HOO H
, ,
103821 In some embodiments, R is:
SH
)0,Ly. jiyH
SH NH2 N);
HO N
Hs"---,si ---/ HS'---)41 NH2 " 0
,
SH 0 e
NC11/
0 =- 0
cskA N ,,,,sirH SA 0
rSH
N''--)OH 1..,.õ..,,,... )----µ0
HS
H
Fr\ii-/ /
NH2 0 HS
OH
0 0
0 's)-3
Ha N
Ir1,1
-...,r0 0 S,s '--)
HO- ./
00 S
HN ,s
_k._,..õ.õ 1 ...,s.,..S
5,S.,,,.,,L__,=¨=,,õ---1
,-.:==,.
HO 0
¨91¨
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
o
HSõ----...õõNH
0 NH2
HO)"LrS'Sss,
NH2 HO 0
0
>(SN.--assssss
N N H
0 0 , or HS
[0383] In some embodiments, R is the radical recited in Compound 1
[0384] In some embodiments, R is the radical recited in Compound 2
[0385] In some embodiments, R is the radical recited in Compound 3.
[0386] In some embodiments, R is the radical recited in Compound 4.
[0387] In some embodiments, R is the radical recited in Compound 5.
[0388] In some embodiments, R is the radical recited in Compound 6.
[0389] In some embodiments, R is the radical recited in Compound 7.
[0390] In some embodiments, R is the radical recited in Compound 8A.
[0391] In some embodiments, R is the radical recited in Compound 8B.
[0392] In some embodiments, R is the radical recited in Compound 9A
[0393] In some embodiments, R is the radical recited in Compound 9B.
[0394] In some embodiments, R is the radical recited in Compound 10.
[0395] In some embodiments, R is the radical recited in Compound 11.
[0396] In some embodiments, R is the radical recited in Compound 12.
[0397] In some embodiments, R is the radical recited in Compound 13.
[0398] In some embodiments, R is the radical recited in Compound 14
[0399] In some embodiments, R is the radical recited in Compound 15.
[0400] In some embodiments, R is the radical recited in Compound 16.
[0401] In some embodiments, R is the radical recited in Compound 17.
[0402] In some embodiments, R is the radical recited in Compound 18.
[0403] In some embodiments, R is the radical recited in Compound 19.
104041 In some embodiments, R is the radical recited in Compound 20.
[0405] In some embodiments, R is the radical recited in Compound 24.
[0406] In some embodiments, R is the radical recited in Compound 25.
[0407] In some embodiments, R is the radical recited in Compound 26.
-92-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0408] In some embodiments, R is the radical recited in Compound 27.
[0409] In some embodiments, R is the radical recited in Compound 28.
[0410] In some embodiments, R is the radical recited in Compound 29.
[0411] In some embodiments, R is the radical recited in Compound 30.
[0412] In some embodiments, R is the radical recited in Compound 31.
[0413] In some embodiments, R is the radical recited in Compound 32.
[0414] In some embodiments, R is the radical recited in Compound 33.
[0415] In some embodiments, R is the radical recited in Compound 34
[0416] In some embodiments, R is the radical recited in Compound 35.
[0417] In some embodiments, R is the radical recited in Compound 36.
[0418] In some embodiments, R is the radical recited in Compound 37.
[0419] In some embodiments, R is the radical recited in Compound 38.
[0420] In some embodiments, R is the radical recited in Compound 39.
[0421] In some embodiments, R is the radical recited in Compound 40.
[0422] In some embodiments, R is the radical recited in Compound 41.
[0423] In some embodiments, R is the radical recited in Compound 42.
[0424] In some embodiments, R is the radical recited in Compound 43.
[0425] In some embodiments, R is the radical recited in Compound 44.
[0426] In some embodiments, R is the radical recited in Compound 45.
[0427] In some embodiments, R is the radical recited in Compound 46.
[0428] In some embodiments, R is the radical recited in Compound 47.
[0429] In some embodiments, R is the radical recited in Compound 48.
104301 In some embodiments, provided herein is a compound having the structure
of Formula
(Ib)
0=S=0
0 CI
,Lz-0
Rx
0
CI 0
0
Formula (lb)
or a pharmaceutically acceptable salt thereof,
wherein:
-93-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Lz is bond, -0(C=0)(OCR8R9)7-, or -(C=0)(OCR8R9)7-;
each le and R9 is independently H, halogen, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6; and
Rx is:
R2c R2d
R2a
R2b
was m
eo2
0 Fµ
R1 bs
R2f
Rla and Rib are each independently -H or -SR';
each Ric is independently substituted or unsubstituted (e.g., straight or
branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, and optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3
alkyl);
each R2a, R2b, R2c, R2d, R2e, and R2f is independently H, halogen, CI-C3-
alkyl, CI-
C3-haloalkyl, C1-C3-alkoxy, C3-05-cycloalkyl, or two of R2a and R2b, R2' and
R2d, or R2e and R2f are taken together with the atoms to which they are
attached
to form a C3-05-cycloalkyl;
m is an integer from 1-10; and
n and o are each independently an integer from 1-3.
104311 In some embodiments, o is 0.
104321 In some embodiments, o is 0, and Rx is:
pp2c D2d
59c2b
R1as m
Ribs
-94-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0433] In some embodiments, o is 0 and n is 1.
[0434] In some embodiments, o is 0, n is 1, and Rx is:
0.2c Do2d
R,2)92b
RlaS misss
Ribs
[0435] In some embodiments, m is an integer from 3-5.
[0436] In some embodiments, each R2a, R2b, R2c, Rat, R2e, and R2f is
independently H, halogen,
Ci-C3alkyl, or Ci-C3haloalkyl. In some embodiments, each R2a, 2R b, R2c, R2d,
R2C, and It2f is H.
[0437] In some embodiments, Rx is:
sR"
R1 as 45
,
wherein:
Rla and Rth are each independently -H or -SR1c; and
each Ricis independently substituted or unsubstituted (e.g., straight or
branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3
alkyl).
[0438] In some embodiments, lea is -H or -SR" and Rib is -SR", or Rla is -SR"
and Rib is -H or
-SR". In some embodiments, Rla and Rth are each -SR'.
[0439] In some embodiments, Rla and Rib are each independently a radical of
one or more
keratolytic group (e.g., each radical of the one or more keratolytic group
being independently
selected from the group consisting of a radical of glycolic acid (GA), a
radical of thioglycolic acid
(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a
radical of lipoic acid
(Lip), a radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic
acid (diHLip), a radical
of lipoic acid sulfonyl (Lipsulf), a radical of N-acetyl cysteine (NAC), a
radical of cysteine (Cys),
a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of
bucillamine (Buc)).
-95-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
104401 In some embodiments, Ria and Rib each independently comprise a radical
of one or more
keratolytic group (e.g., each radical of the one or more keratolytic group
being independently
selected from the group consisting of a radical of glycolic acid (GA), a
radical of thioglycolic acid
(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a
radical of lipoic acid
(Lip), a radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic
acid (diHLip), a radical
of N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of
glutathione (G SIT), a radical
of captopril (Cap), and a radical of bucillamine (Buc)).
104411 In some embodiments, RI-a and Rib are each independently a radical of
one or more
keratolytic group, each radical of the one or more keratolytic group being
independently selected
from the group consisting of a radical of glycolic acid (GA), a radical of
thioglycolic acid (TGA),
a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a radical
of lipoic acid (Lip), a
radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic acid
(diHLip), a radical of N-
acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of glutathione
(GSH), a radical of
captopril (Cap), and a radical of bucillamine (Buc).
104421 In some embodiments, Ria and Rib each independently comprise a (thiol)
radical of one or
more keratolytic group, each (thiol) radical of the one or more keratolytic
group being
independently selected from the group consisting of a (thiol) radical of
thioglycolic acid (TGA),
a (thiol) radical of thiolactic acid (TLac), a (thiol) radical of
dihydrolipoic acid (diHLip), a (thiol)
radical of N-acetyl cysteine (NAC), a (thiol) radical of cysteine (Cys), a
(thiol) radical of
glutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol) radical
of bucillamine (Buc).
104431 In some embodiments, RI-a and Rib are each independently a thiol
radical of one or more
keratolytic group, each thiol radical of the one or more keratolytic group
being independently
selected from the group consisting of a thiol radical of thioglycolic acid
(TGA), a thiol radical of
thiolactic acid (TLac), a thiol radical of dihydrolipoic acid (diHLip), a
thiol radical of N-acetyl
cysteine (NAC), a thiol radical of cysteine (Cys), a thiol radical of
glutathione (GSH), a thiol
radical of captopril (Cap), and a thiol radical of bucillamine (Buc).
104441 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC]., [diHLip-NAC], [diHLip-Cap-Cap].,
[diFILip-Cap],
[diHLip-Cys-Cys]=, [diHLip-Cys]-, [diHLip-Lipox-Lipox]-, and [diHLip-Lipox]-.
104451 Unless stated otherwise, a radical (or.) is molecule having unpaired
electrons. In some
embodiments, the radical is a radical of a heteroatom (e.g., -0-,
or -S-). In some embodiments,
-96-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
the radical (e.g., the molecule having unpaired electron) is paired with
another unpaired electron
of another molecule to form paired electrons. In some embodiments, a radical
of a keratolytic
agent provided herein is paired with any compound provided herein. In some
embodiments, a first
radical of a keratolytic agent provided herein is paired with a second radical
of a keratolytic
provided herein.
104461 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
Of Ria and/or Rib to the rest of the molecule. In some embodiments, Ria and/or
Rib attach to the
rest of the molecule to form a disulfide bond
104471 In some embodiments, Ria and Rib are each independently -H or:
)22Z
HS
sr( s_Thr.OH OHs/s-s OH HSOH
0
clirOH
)(NH NH2 0 0 0
0
`2,27:-.S.õ,õTrOH
OH S
0 0 NH2 0
o
SH
0 0 0 0
\,S7(1t,N,ThrOH HSKIL,N,Thr-OHOH
0 0 , or 0
104481 In some embodiments, RI' and Rib are the same. In some embodiments, RI
and Rib are
different.
104491 In some embodiments, IV is:
R1cs,
R -lc-
s
wherein:
each Ric is independently substituted or unsubstituted (e.g., straight or
branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
-97-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH)) or
substituted or unsubstituted (e.g., straight or branched) heteroalkyl (e.g.,
substituted with one or more (heteroalkyl) sub stituent, each (heteroalkyl)
substituent being independently selected from the group consisting of
carboxylic acid, amino, thioalkyl, thiol, acetamide, and C I-C3 alkyl).
[0450] In some embodiments, each R" is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or unsubstituted (e.g., straight or
branched) heteroalkyl. In some
embodiments, each Ric is independently substituted (es , straight or branched)
alkyl or substituted
(e.g., straight or branched) heteroalkyl.
[0451] In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl)
substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl, acetamide, amino, oxo, and optionally substituted heterocycloalkyl
(e.g., N-attached
pyrrolidinyl substituted with -COOH).
[0452] In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
sub stituent, each (heteroalkyl) sub stituent being independently selected
from the group consisting
of carboxylic acid, amino, thioalkyl, thiol, acetamide, and C1 -C3 alkyl.
[0453] In some embodiments, Rla, Rib, and each Ric each independently comprise
one or more
substituent that is a carboxylic acid or an ester. In some embodiments, Rla,
Rib, and each Ric each
independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H). In
some embodiments, Rla comprises one or more substituent that is a carboxylic
acid (e.g., -
(C=0)0H). In some embodiments, Rib comprises one or more sub stituent that is
a carboxylic acid
(e.g., -(C=0)0H). In some embodiments, each R' independently comprises one or
more
substituent that is a carboxylic acid (e.g., -(C=0)0H). In some embodiments,
Ria, Rib, and each
Ric each independently comprise one or more substituent that is an ester
(e.g., -(C=0)0-Ci-
C4alkyl). In some embodiments, Rla comprises one or more substituent that is
an ester (e.g., -
(C=0)0-Ci-C4alkyl). In some embodiments, Rib comprises one or more sub
stituent that is an ester
(e.g., -(C=0)0-C1-C4alkyl). In some embodiments, each Ric independently
comprises one or more
sub stituent that is an ester (e.g., -(C=0)0-Ci-C4alkyl).
[0454] In some embodiments, the -(C=0)0H of Rh, Rib, and/or Ric is optionally
esterified (e.g.,
-(C=0)0H or -(C=0)0-Ci-C4alkyl).
[0455] In some embodiments, Itx is:
-98-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
OH
0 0
HN
HOIrL1
--y0 0 S.,
0
S,
HN y='*\
HOO or
104561 In some embodiments, provided herein is a compound having the structure
of Formula
(Ic):
0=S=0
0 CI
,Lz-0 =
RY
0
CI 0
0
Formula (Ic)
or a pharmaceutically acceptable salt thereof,
wherein:
Lz is bond, -0(C=0)(OCR8R9)z-, or -(C=0)(OCR8R9)z-,
each R8 and R9 is independently H, halogen, C1-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or le and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6; and
RY is:
R4a R4b
P
each R4a and R4b is independently H, halogen, or substituted or unsubstituted
alkyl;
p is an integer from 1-10; and
q is an integer from 1-3.
104571 In some embodiments, p is an integer from 3-5. In some embodiments, p
is 4. In some
embodiments, q is 1 and p is 4.
-99-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0458] In some embodiments, each R4a and R4b is independently H or substituted
or unsubstituted
alkyl. In some embodiments, each R4a and R4b is independently H, halogen, Ci-
C3alkyl, or C1-
C3haloalkyl. In some embodiments, each R4a and R41' is H.
[0459] In some embodiments, W is:
0
SIS
.r5ss'
[0460] In some embodiments, the sulfoxide of any compound provided herein is
racemic. In some
embodiments, the sulfoxide of any compound provided herein is an enantiomer.
In some
embodiments, the sulfoxide of any compound provided herein is has a
stereochemistry that is (R)
or (S).
[0461] In some embodiments, provided herein is a compound having the structure
of Formula
(Id):
0=S=0
0 CI
,Lz-0
Rz
0
CI 0
0
Formula (Id)
or a pharmaceutically acceptable salt thereof,
wherein:
Lz is bond, -0(C=0)(OCR8R9)z-, or -(C=0)(OCR8R9)z-;
each le and R9 is independently H, halogen, C1-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl,
z is 1-6; and
Rz is:
N R6R7
R5'50
R 1 R11
R5 is -SR',
-100-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Rlc is substituted or unsubstituted (e.g., straight or branched) alkyl (e.g.,
substituted with one or more (alkyl) substituent, each (alkyl) substituent
being independently selected from the group consisting of carboxylic acid,
-SH, thioalkyl, acetamide, amino, oxo, and optionally substituted
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH)),
or substituted or unsubstituted (e.g., straight or branched) heteroalkyl
(e.g.,
substituted with one or more (heteroal kyl) substituent, each (h etero al kyl)
substituent being independently selected from the group consisting of
carboxylic acid, amino, thioalkyl, thiol, acetamide, and C1-C3 alkyl);
R6 and R7 are each independently H, substituted or unsubstituted alkyl, or
substituted or unsubstituted h etero al kyl ;
each Rth and is independently H, halogen, Cl-C3-alkyl,
C1-C3-haloalkyl, Ci-
C3-alkoxy, C3-05-cycloalkyl, or two of Rm and R" are taken together with the
atoms to which they are attached to form a C3-05-cycloalkyl; and
s is an integer from 1-10.
104621 In some embodiments, R6 and R7 are each independently H or substituted
or unsubstituted
alkyl (e.g., C i-C3 alkyl optionally substituted with oxo). In some
embodiments, R6 and R7 are each
independently H or C1-C3 alkyl optionally substituted with oxo. In some
embodiments, R6 and R7
are each independently H or -(C=0)CH3. In some embodiments, R6 is H and R7 is
H or -
(C=0)CH3. In some embodiments, R6 is H and R7 is -(C=0)CH3. In some
embodiments, R6 and
R7 are H.
104631 In some embodiments, each Rl and R" is independently H, halogen, CI-
C3a1kyl, or C1-
C3haloalkyl. In some embodiments, each Rm and R11 is H.
104641 In some embodiments, s is 1-3. In some embodiments, s is 1. In some
embodiments, s is 1
and Rth and R" are H.
104651 In some embodiments, R5 comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
-101-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
104661 In some embodiments, R5 is a radical of one or more keratolytic group,
each radical of the
one or more keratolytic group being independently selected from the group
consisting of a radical
of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical of
lactic acid (Lac), a radical
of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical of lipoic
acid sulfoxide (Lipox),
a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine
(NAC), a radical of cysteine
(Cys), a radical of glutathione (GSM, a radical of captopril (Cap), and a
radical of bucillamine
(Buc).
104671 In some embodiments, R5 comprises a (thiol) radical of one or more
keratolytic group,
each (thiol) radical of the one or more keratolytic group being independently
selected from the
group consisting of a (thiol) radical of thioglycolic acid (TGA), a (thiol)
radical of thiolactic acid
(TLac), a (thiol) radical of dihydrolipoic acid (diHLip), a (thiol) radical of
N-acetyl cysteine
(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical of glutathione
(GSH), a (thiol) radical
of captopril (Cap), and a (thiol) radical of bucillamine (Buc).
104681 In some embodiments R5 is a thiol radical of one or more keratolytic
group, each thiol
radical of the one or more keratolytic group being independently selected from
the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
104691 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]-, [Lac-
NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC], [diHLip-NAC],
[diHLip-Cap],
[diHLip-Cys-Cys]., [diHLip-Cys]., [diHLip-Lipox-Lipox]=, and [diHLip-Lipox]...
104701 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of R5 to the rest of the molecule. In some embodiments, R5 attaches to the
rest of the molecule to
form a disulfide bond.
104711 In some embodiments, R5 is:
-102-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
ss55-.
HS
A. OH }..,(OH ssss'''s OH HS
OH
0
)LNH NH2 0 0 0
0
OH \,S..,.../Ly01-1
OH S
0
SNH
SH
0 0 00
\-S7c11..N...--.1r0H HSNOH
0 0 , or 0
104721 In some embodiments, Rz is:
NHR7
104731 In some embodiments, R7 is H or -(C=0)CH3. In some embodiments, R7 is
H. In some
embodiments, R7 is -(C=0)CEL.
104741 In some embodiments, each Ric is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or unsubstituted (e.g., straight or
branched) heteroalkyl. In some
embodiments, each Fe is independently substituted (e.g., straight or branched)
alkyl or substituted
(e.g., straight or branched) heteroalkyl.
104751 In some embodiments, each R1c is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl)
substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl, acetamide, amino, oxo, and optionally substituted heterocycloalkyl
(e.g., N-attached
pyrrolidinyl substituted with -COOH).
104761 In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
substituent, each (heteroalkyl) substituent being independently selected from
the group consisting
of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl.
-103-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
104771 In some embodiments, R5 and each RI each independently comprise one or
more
substituent that is a carboxylic acid or an ester. In some embodiments, R5 and
each Ric each
independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H). In
some embodiments, R5 and each Ric each independently comprise one or more
substituent that is
an ester (e.g., -(C=0)0-CI-C4alkyl).
104781 In some embodiments, the -(C=0)OII of R5 and/or Rlc is optionally
esterified (e.g., -
(C=0)0H or -(C=0)0-C1-C4alkyl) In some embodiments, the C1-C4alky1 is methyl,
ethyl,
propyl, isopropyl, butyl, or t-butyl
104791 Provided in some embodiments herein is a compound having a structure
provided in Table
1, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of
the compound or the
stereoi somer.
Table 1
0=S=0
0 CI
IR/Lz¨O
0
CI 0
0
Compoun
Lz
1
HS"
-(C=0)0CH(CH3)-
SH
2 -(C=0)0CH(CH3)-
SH
3 -(C=0)0CH(CH3)-
NH2
4 HS/ -(C=0)0 CH(CH3)-
0
-)L-N1H -(C=0)0CH(CH3)-
HS ..-.5sssN
8
,0
C
S¨s
6 C) -(C=0)0CH(CH3)-
-104-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
,o
S-S
7 -(C=0)0CH(CH3)-
00
8A CDµS-S -(C=0)0CH(CH3)-
o
8B e's_s
-(C=0)0CH(CH3)-
o
9A Gh_s
-(C=0)0CH(CH3)-
oe
9B 0µs_s
0
-(C=0)0CH(CH3)-
s H
0
H
HO N N =z, ¨(C=0)0CH(CH3)¨
11
ICI H2 0
SH
sssss0
¨(C=0)0CH(CH3)¨
OH
NI-12 0
(SH
0
12 HS\)LNCsf -(C=0)0CH(CH3)-
0
SH
_
13 HSx-11Ni -(C=0)0CH(CH3)-
,
H
14 CN-DS
-(C=0)0CH(CH3)-
HS
Oy-
HSaN
-(C=0)0CH(CH3)-
0 0
00'Y
-105-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
Oy-
N H
HS
16 -(C=0)0CH(CH3)-
0 0
0
H N
HOõiiõ1õ1
17 0 S -(C=0)0CH(CH3)-
,s
HO 0
0
H N
HOI.rA.1
18 0 S -(C=0)0CH(CH3)-
HO 0
OH
0
00x,11,,/
19 -(C=0)0CH(CH3)-
S,s
HO 00
S S
OH
0.01.1V
20 ;1
-(C=0)0CH(CH3)-
0 ,s
HO 0 S
0 N H2
21 -(C=0)0CH(CH3)-
N H2
-106-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
,o
22 S¨S
bond
,o
23 S¨S
\ ¨0(C=0)0CH(CH3)¨
sr
24 -(C=0)0CH(CH3)-
NH
25 -(C=0)0CH(CH3)-
HO 0
><SD
26 N -(C=0)0CH(CH3)-
0
27 N¨Vs ¨(C=0)0CH(CH3)-
0
28 _(c=o)ocH(cH3)-
29
0
CH(CH3)0(C=0)0(CH2CH20)4(C=0)
HS
30 1(
0
CH(CE-13)0(C=0)0(CH2CH20)8(C=0)
HS
31 -(C=0)0CH(CH3)-
0
6A -(C=0)0CH(CH3)-
õo
7A -(C=0)0CH(CH3)-
sr
-107-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
SY11(
0
0
49 ,seo -
(c=o)ocH(cH3)-
0 0 0
CI 0
/
0 ci N
0
104801 Provided in some embodiments herein is a compound having a structure
provided in Table
2, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of
the compound or the
stereoisomer.
Table 2
0=S=0
0 CI
IR HIN
/Lz-0
0
CI 0
0
Compound
32 HO bond
33 H bond
34 -
(C=0)0CH2CH2-
35 -(C=0)0CH2CH2CH2-
36 -(C=0)0CH2-
3 7 -(C=0)0CH(CH3)-
0
3 8 y -(C=0)0CH2-
0
39 e -(C=0)0CH2-
-108-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
S -S1=1
40 -(C=0)0CH2-
r, 0
1/4-1,Z, I I
S¨s
41 -(C=0)0CH2-
42 -0(C=0)0CH(CH3)-
43 -0(C=0)0CH(CH3)-
SOH
44 HN
-(C=0)0CH(CH3)-
0
0
0 OH
H
45 -(C=0)0CH(CH3)-
0
S¨s
46 -0(C=0)0CH(CH3)-
cs'
0
0
47 .so
S -0(C=0)0CH(CH3)-
48 -(C=0)0CH(CH3)-
sts
c)y104811 Each recitation of" "provided herein, unless otherwise stated,
includes a specific
and explicit recitation of
0 e 0 0
S--' o e
S-S s-s' s-s' s-s
cA,s' U),re
, and
104821 The compounds used in the reactions described herein are made according
to organic
synthesis techniques starting from commercially available chemicals and/or
from compounds
described in the chemical literature or provided herein. "Commercially
available chemicals" are
obtained from standard commercial sources including Acros Organics
(Pittsburgh, PA), Aldrich
Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals
Ltd (Milton
-109-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada),
Bionet
(Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co.
(Hauppauge,
NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher
Scientific
Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier
Scientific (Logan, UT),
ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.),
Lancaster Synthesis
(Windham, NIT), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical
Co. (Orem,
UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce
Chemical Co.
(Rockford, 11,), Riedel de Haen AG (Hanover, Germany), Spectrum Quality
Product, Inc. (New
Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc.
(Rockville, MD), and
Wako Chemicals USA, Inc. (Richmond, VA).
104831 Suitable reference books and treatise that detail the synthesis of
reactants useful in the
preparation of compounds described herein, or provide references to articles
that describe the
preparation, include for example, "Synthetic Organic Chemistry-, John Wiley &
Sons, Inc., New
York; S. R. Sandler et al., "Organic Functional Group Preparations," 2' Ed.,
Academic Press,
New York, 1983; H. 0. House, "Modern Synthetic Reactions", 2nd Ed., W. A.
Benjamin, Inc.
Menlo Park, Calif 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed.,
John Wiley & Sons,
New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms
and
Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable
reference books and
treatise that detail the synthesis of reactants useful in the preparation of
compounds described
herein, or provide references to articles that describe the preparation,
include for example,
Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second,
Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5;
Hoffman, R.V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-
5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional
Group
Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.
"Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure- 4th Edition (1992)
John Wiley &
Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry"
(2000) Wiley-VCH,
ISBN: 3-527-2987 1 -1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups"
(1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry-
7th Edition
(2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate
Organic
Chemistry" 2' Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;
"Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann' s Encyclopedia"
(1999) John Wiley
& Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000)
John Wiley &
-3_10-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley &
Sons, in 73
volumes.
104841 Specific and analogous reactants are optionally identified through the
indices of chemicals
prepared by the Chemical Abstract Service of the American Chemical Society,
which are available
in most public and university libraries, as well as through on-line databases
(contact the American
Chemical Society, Washington, D.C. for more details). Chemicals not
commercially available in
catalogs are optionally prepared by custom chemical synthesis houses, where
many of the standard
chemical supply houses (e g , those listed above) provide custom synthesis
services A reference
for the preparation and selection of pharmaceutical salts of the keratolytic
conjugate described
herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts",
Verlag Helvetica
Chimica Acta, Zurich, 2002.
104851 In some embodiments, a compound provided herein is represented by any
one of Formula
(I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula (Ic),
Formula (Id), Formula (I-
A), Formula (I-B), Formula (I-C), Table 1, or Table 2. In some embodiments, a
compound
provided herein is administered as a pure chemical. In other embodiments, a
compound provided
herein is combined with a pharmaceutically suitable or acceptable carrier
(also referred to herein
as a pharmaceutically suitable (or acceptable) excipient, physiologically
suitable (or acceptable)
excipient, or physiologically suitable (or acceptable) carrier) selected on
the basis of a chosen
route of administration and standard pharmaceutical practice as described, for
example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub.
Co., Easton, PA
(2005)).
104861 Provided in some embodiments herein is a pharmaceutical composition
comprising at least
one keratolytic conjugate together with one or more pharmaceutically
acceptable carriers. The
carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is
compatible with the other
ingredients of the composition and not deleterious to the recipient (i.e., the
subject) of the
composition.
104871 In some embodiments, a compound provided herein (e.g., a compound
having a structure
represented by any one of Formula (I), Formula (I'), Formula (I), Formula
(Ia), Formula (Ib),
Formula (Ic), Formula (Id), Formula (I-A), Formula (T-B), Formula (I-C), Table
1, or Table 2) is
substantially pure, in that it contains less than, for example, about 5%, or
less than about 1%, or
less than about 0.1%, of other organic small molecules, such as unreacted
intermediates or
synthesis by-products that are created, for example, in one or more of the
steps of a synthesis
method.
-111-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
104881 Suitable oral dosage forms include, for example, tablets, pills,
sachets, or capsules of hard
or soft gelatin, methylcellulose or of another suitable material easily
dissolved in the digestive
tract. In some embodiments, suitable nontoxic solid carriers are used which
include, for example,
pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium
saccharin, talcum,
cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,
_Remington: The Science
and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA
104891 (2005)).
104901 In some embodiments provided herein is a pharmaceutical composition
comprising a
compound provided herein (e.g., a compound having a structure represented by
such a any one of
Formula (I), Formula (I'), Formula (I), Formula (Ia), Formula (lb), Formula
(Ic), Formula (Id),
Formula (I-A), Formula (I-B), Formula (I-C), Table 1, or Table 2) and at least
one
pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical
composition is
suitable for ophthalmic administration. In some embodiments, the
pharmaceutical composition is
suitable for topical ophthalmic administration. In some embodiments, topical
ophthalmic
administration is administration in and/or around the eye, such as to the
eyelid margin. In some
embodiments, topical ophthalmic administration is administration to the ocular
surface and the
inner surface to the eyelid.
104911 In some embodiments, a keratolytic conjugate provided herein (e.g., a
compound having
a structure represented any one of Formula (I), Formula (I'), Formula (I),
Formula (Ia), Formula
(Ib), Formula (Ic), Formula (Id), Formula (1-A), Formula (I-B), Formula (1-C),
Table 1, or Table
2) is formulated as a solution or suspension for topical administration to the
eye.
104921 In some embodiments, a keratolytic conjugate provided herein (e.g., a
compound having
a structure represented by any one of Formula (I), Formula (I'), Formula (I),
Formula (Ia), Formula
(lb), Formula (Ic), Formula (Id), Formula (I-A), Formula (I-B), Formula (I-C),
Table 1, or Table
2) is formulated for administration by injection. In some instances, the
injection formulation is an
aqueous formulation. In some instances, the injection formulation is a non-
aqueous formulation.
In some instances, the injection formulation is an oil-based formulation, such
as sesame oil, or the
like.
104931 In some embodiments, the dose of the composition comprising at least
one keratolytic
conjugate as provided herein differ, depending upon the patient's (e.g.,
human) condition, that is,
general health status, age, and other factors.
104941 Pharmaceutical compositions provided in some embodiments herein are
administered in a
manner appropriate to the disease to be treated (or prevented). An appropriate
dose and a suitable
-112-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
duration and frequency of administration will be determined by such factors as
the condition of
the patient, the type and severity of the patient's disease, the particular
form of the active
ingredient, and the method of administration. In general, an appropriate dose
and treatment
regimen provides the composition(s) in an amount sufficient to provide
therapeutic and/or
prophylactic benefit (e.g., an improved clinical outcome, such as more
frequent complete or partial
remissions, or longer disease-free and/or overall survival, or a lessening of
symptom severity).
Optimal doses are generally determined using experimental models and/or
clinical trials The
optimal dose depends upon the body mass, weight, or blood volume of the
patient
104951 In other embodiments, the topical compositions described herein are
combined with a
pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically
suitable (or acceptable)
excipient, physiologically suitable (or acceptable) excipient, or
physiologically suitable (or
acceptable) carrier). Exemplary excipients are described, for example, in
Remington: The Science
and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
Methods of Treatment Utilizing Keratolytic Conjugates
104961 In some embodiments provided herein is a method of treating a
dermatological or
ophthalmic disease or disorder in a patient in need of thereof, comprising
administering to the
patient any compound provided herein, or a pharmaceutically acceptable salt
thereof, or a (e.g.,
pharmaceutical) composition comprising any compound provided herein, such as a
compound
represented by any one of Formula (I), Formula (I'), Formula (I), Formula
(Ia), Formula (Ib),
Formula (Ic), Formula (Id), Formula (I-A), Formula (I-B), Formula (I-C), Table
1, Table 2, or a
pharmaceutically acceptable salt thereof. In some embodiments provided herein
the
pharmaceutical composition is in the form of a solution or suspension suitable
for topical
ophthalmic administration. In some embodiments, topical ophthalmic
administration is
administration in and/or around the eye, such as to the eyelid margin. In some
embodiments,
topical ophthalmic administration is administration to the ocular surface and
the inner surface to
the eyelid.
104971 In some embodiments, the dermatological or ophthalmic disease or
disorder is
inflammation or hyperkeratosis (e.g., of the eyes or skin). In some
embodiments, the
dermatological or ophthalmic disease or disorder is inflammation or
hyperkeratosis of the eyes or
skin (e.g., the ocular surface). In some embodiments, the dermatological or
ophthalmic
dermatological disease or disorder is selected from the group consisting of
meibomian gland
dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft
versus host disease,
vernal keratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de Lange
Syndrome, evaporative
-113-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
eye disease, aqueous deficiency dry eye, blepharitis, and seborrheic
blepharitis. In some
embodiments, the dermatological or ophthalmic disease or disorder is
inflammation or
hyperkeratosis (e.g., of the eyes or skin), such as, for example, meibomian
gland dysfunction
(MGD), dry eye disease (DED), ocular manifestations of graft versus host
disease, vernal
keratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de Lange Syndrome,
evaporative eye
disease, aqueous deficiency dry eye, blepharitis, seborrheic blepharitis, or
any combination
thereof.
104981 In some embodiments, the ophthalmic disease or disorder is selected
from the group
consisting of dry eye, lid wiper epitheliopathy (LWE), contact lens discomfort
(CLD), dry eye
syndrome, evaporative dry eye syndrome, aqueous deficiency dry eye syndrome,
blepharitis,
keratiti s, m eibomi an gland dysfunction, conjunctivitis, lacrimal gland
disorder, contact lens
related conditions and inflammation of the anterior surface of the eye,
infection of the anterior
surface of the eye, and autoimmune disorder of the anterior surface of the
eye.
104991 Provided herein is a method for treating an ocular surface disorder in
an individual in need
thereof comprising topical administration of a keratolytic conjugate to the
individual in need
thereof. In some embodiments, administration occurs with the assistance of a
health-care provider
(e.g., this category includes both acute and maintenance uses of the
keratolytic conjugate). An
acute use, in some embodiments, requires a stronger keratolytic conjugate
(either in terms of
concentration of the agent or the inherent activity of the agent). A
maintenance use, in some
embodiments, allows for the use of lower concentrations of the agent, or
agents with lower
inherent activity. A maintenance use, in some embodiments, involves a patient
at a routine visit
to the health care provider. Both acute uses and maintenance uses optionally
involve use of an
eye-protecting device or apparatus. In some embodiments, the acute use is
performed by the health
care provider, and the maintenance use is performed by the patient or non-
health care provider. In
some embodiments, administration does not occur with the active assistance of
a health care
provider (e.g., but rather involves the patient applying the keratolytic
conjugate to his/her own
eyelid margin). In some embodiments, such administration occurs over an
extended period of time
(e.g., one way of describing this patient-administered multi-administration
mode is as a chronic
use). In some embodiments, different or second formulations of the keratolytic
conjugate are used
for chronic or patient-administered uses. In some embodiments the different or
second formulation
utilizes a lower concentration of the keratolytic conjugate. In some
embodiments, the second or
different formulation utilizes a keratolytic conjugate that has a lower
activity than the first
formulation.
-114-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
105001 It should be understood that the present methods also include the
physical removal of an
obstruction in an meibomian gland (e.g., followed by chronic and/or
maintenance administration
of a keratolytic conjugate provided herein).
105011 In some embodiments provided herein is a method for treating meibomian
gland
dysfunction in a patient in need thereof, comprising topically administering
to the patient a
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate in
an ophthalmically-acceptable carrier. In some embodiments, the topical
administration of the
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate in
an ophthalmically-acceptable carrier results in enhanced meibum production.
105021 In some embodiments, the topical administration of the composition
comprising a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmically-
acceptable carrier occurs until the keratinized obstruction is relieved. In
some embodiments, the
topical administration of the composition comprising a therapeutically-
effective amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier occurs
periodically after
relieving of the keratinized obstruction. In some embodiments, the topical
administration of the
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate in
an ophthalmically-acceptable carrier is a single administration. In some
embodiments, the topical
administration of the composition comprising a therapeutically-effective
amount of at least one
keratolytic conjugate in an ophthalmically-acceptable carrier is a periodic
administration. In some
embodiments, the topical administration of the composition comprising a
therapeutically-effective
amount of at least one keratolytic conjugate in an ophthalmically-acceptable
carrier occurs once
a day. In some embodiments, the topical administration of the composition
comprising a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmically-
acceptable carrier occurs twice a day. In some embodiments, the topical
administration of the
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate in
an ophthalmically-acceptable carrier occurs more than twice a day.
105031 In some embodiments, the composition for topical administration
comprises a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmically-
acceptable carrier is a solution. In some embodiments, the composition for
topical administration
comprises a therapeutically-effective amount of at least one keratolytic
conjugate in an
ophthalmically-acceptable carrier is a solution suitable for topical
administration as eye drops. In
some embodiments, the composition for topical administration comprises a
therapeutically-
effective amount of at least one keratolytic conjugate in an ophthalmically-
acceptable carrier is a
-115-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
gel, ocular insert, spray, or other topical ocular delivery method. In some
embodiments, the
composition for topical administration comprises a therapeutically-effective
amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier is a semi-
solid. In some
embodiments, the composition for topical administration comprises a
therapeutically-effective
amount of at least one keratolytic conjugate in an ophthalmically-acceptable
carrier is
homogenous. In some embodiments, the composition for topical administration
comprises a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophth al m i cally-
acceptable carrier is a dispersion In some embodiments, the composition for
topical
administration comprises a therapeutically-effective amount of at least one
keratolytic conjugate
in an ophthalmically-acceptable carrier is hydrophilic. In some embodiments,
the composition for
topical administration comprises a therapeutically-effective amount of at
least one keratolytic
conjugate in an ophthalmically-acceptable carrier and an oleaginous base. In
some embodiments,
the composition for topical administration comprises a therapeutically-
effective amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier and at least
one ophthalmically-
acceptable excipient.
105041 In some embodiments provided herein is a method for treating MGD in a
patient in need
thereof comprising topical administration of a composition comprising a
keratolytic conjugate. In
some embodiments, the topical administration of the composition comprising a
keratolytic
conjugate occurs once a week. In some embodiments, the topical administration
of the
composition comprising a keratolytic conjugate occurs twice a week. In some
embodiments, the
topical administration of the composition comprising a keratolytic conjugate
occurs every other
day. In some embodiments, the topical administration of the composition
comprises a keratolytic
conjugate occurs every day. In some embodiments, the topical administration of
the composition
comprises a keratolytic conjugate occurs several times a day.
[0505] In some embodiments, the method comprises administering a compound or
formulation
provided herein in an acute treatment scenario. In some embodiments, the
method comprises
treatment of a patient naive to treatment. In some embodiments, the method
comprises
administering a compound or formulation provided herein in a chronic treatment
scenario. In some
embodiments, the method comprises administering a compound or formulation
provided herein
in a maintenance therapy scenario. In an acute treatment scenario, the
administered dosage of
keratolytic conjugate may be higher than the administered dosage of
keratolytic conjugate
employed in a chronic treatment scenario or a maintenance therapy scenario. In
an acute treatment
scenario, the keratolytic conjugate may be different from the keratolytic
conjugate employed in a
-116-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
chronic treatment scenario. In some embodiments, the course of therapy begins
in the initial phase
of therapy as an acute treatment scenario and later transitions into a chronic
treatment scenario or
a maintenance therapy scenario. In some embodiments, the meibomian gland
opening
pharmacological agent administered in the acute treatment scenario is a
keratolytic agent and/or
keratoplastic agent, and the pharmacological agent administered in the chronic
treatment scenario
or a maintenance therapy scenario is a keratolytic conjugate.
105061 In some embodiments, an initial treatment is administered (e.g., by a
physician or
healthcare professional) to an individual to initially open a blockage of the
meibomian gland, such
as by placing a more highly concentrated formulation of one of the keratolytic
conjugate provided
herein. In the event the higher concentration formulations are required, the
application thereof
may require ocular shielding or other activity to minimize the impact of
irritation or disruption of
the ocular surface or surrounding tissues. Following such a procedure, a
patient may be given a
different formulation of keratolytic conjugate to take home to apply
periodically to the lid margin
to maintain the patency of the meibomian gland. Such application may occur
twice daily, once a
day, weekly or monthly, depending on the formulation activity and the
therapeutic product profile
of the formulation.
105071 Provided in some embodiments of the methods of treatment described
herein is the location
of the topical administration of the composition. In some embodiments, the
composition
comprising a keratolytic conjugate is administered such that no irritation to
eye occurs. In some
embodiments, the composition comprising a keratolytic conjugate is
administered to the eye lid
margin.
105081 In some embodiments of the methods of treatment provided herein is the
use of a protective
element provided to the eye to avoid irritation to the eye. Although the
formulations described
herein are generally non-irritating, in some embodiments (e.g., high
concentration of agent or
when used on a sensitive eye) a protective element provides an additional
layer of safety and
comfort for the patient. In some embodiments, the composition comprising a
keratolytic conjugate
is administered while an eye shield is placed on the eye to reduce contact of
the pharmacological
agent with the cornea and/or conjunctiva such that reduced irritation to eye
occurs. In some
embodiments, the eye shield is a contact lens or an eye covering. In some
embodiments, the eye
covering comprises a self-adhesive. In some embodiments, the composition
comprising a
keratolytic conjugate is administered while the lid is pulled away from the
globe to reduce contact
of the pharmacological agent with the cornea and/or conjunctiva such that
reduced irritation to
eye occurs.
-117-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
105091 While preferred embodiments of the present invention have been shown
and described
herein, it will be obvious to those skilled in the art that such embodiments
are provided by way of
example only. Numerous variations, changes, and substitutions will now occur
to those skilled in
the art without departing from the invention. It should be understood that
various alternatives to
the embodiments of the invention described herein may be employed in
practicing the invention.
It is intended that the following claims define the scope of the invention and
that methods and
structures within the scope of these claims and their equivalents be covered
thereby.
EXAMPLES
I. Chemical Synthesis
105101 Solvents and starting reagents and materials were purchased from
commercial vendors and
used as received unless otherwise described. All reactions were performed at
room temperature
unless otherwise stated. Starting reagents and materials were purchased from
commercial sources
or synthesized according to the methods described herein or using literature
procedures or present
procedures provided herein.
Abbreviations
105111 The following abbreviations are used in the Examples and other parts of
the description:
CDCh: deuterated chloroform
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC: dicyclohexyl carbodiimide
DCM: dichloromethane
DIPEA : sopropyl ethyl amine
DMAP: 4-dimethylaminopyridine
DME: /V,N-dimethylformamide
DMSO-d6: dimethyl sulfoxide-d6
Et0Ac: ethyl acetate
HC1: hydrochloric acid
I-170: water
HPLC: high performance liquid chromatography
LCMS: liquid chromatography-mass spectrometry
MeCN: acetonitrile
MeOH: methanol
MgSO4 : magnesium sulfate
min: minute(s)
-118-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
N2: nitrogen
NaHCO3: sodium bicarbonate
Na2SO4: sodium sulfate
NE-14C1: ammonium chloride
Rt: retention time
r.t.: room temperature
sat.: saturated
TFA: trifluoroacetic acid
THE tetrahydrofuran
THP: tetrahydropyran
Analytical Methods:
[0512] Method A: Phenomenex Gemini C18 5 pm, 150 x 4.6 mm; A = water + 0.1%
formic acid;
B = Me0H; 40 C; %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1
min 5%, 13.0
min 5%; 1.5 mL/min.
[0513] Method B: Phenomenex Luna C18 (2) 3 pm, 50 x 4.6 mm; A = water + 0.1%
formic acid;
B = Me0H + 0.1% formic acid; 45 C; %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min
95%, 3.5 min
95%,3.51 min 5%, 4.0 min 5%; 2.25 mL/min.
[0514] Method C: Phenomenex Luna C18 (2) 5 pm, 150 x 4.6 mm; A = water + 0.1%
formic acid;
B = MeCN, 40 C; %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1
min 5%, 13.0
min 5%; 1.50 mL/min.
[0515] Method D: Phenomenex Luna C18 (2) 3 pm, 50 x 4.6 mm; A = water pH 9
(ammonium
bicarbonate 10 mM); B = Me0H; 45 C; %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min
95%, 3.5 min
95%, 3.51 5%, 4.0 min 5%; 2.25 mL/min.
[0516] Method E: Waters Sunfire C18 3.5 pm, 50 x 4.6 mm; A = water + 0.1%
formic acid; B =
MeCN; 40 C; %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%,3.51 min
5%, 4.0 min
5%; 2.25 mL/min.
105171 Method F: QC AnalpH2 MeCN 8MIN: ACQUITY UPLC CSH C18 1.7 pm, 100 x 2.1
mm; A = water + 0.1% formic acid; B = MeCN; 45 C; %B: 0.0 min 5% 0.35 mL/min,
0.05 min
5% 0.35 mL/min, 5 min 95% 0.35 mL/min, 6.5 min 95% 0.35 mL/min, 6.6 min 5%
0.35 mL/min,
9 min 5% 0.35 mL/min.
[0518] Method G: AnalpH2 MeCN 2MIN: ACQUITY UPLC BEH C18 1.7 pm, 50 x 2.1 mm;
A = water + 0.1% formic acid; B = MeCN; 45 C; %B: 0.0 min 5% 0.6 mL/min, 0.05
min 5% 0.6
-119-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
mL/min, 1.6 min 95% 0.6 mL/min, 2.25 min 95% 0.75 mL/min, 2.26 min 5% 0.6
mL/min, 2.6
min 5% 0.6 mL/min.
Chemical Synthesis Example I-1:
105191 1-((lsopropoxycarbonyl)oxy)ethyl
(2,5)-2-(2-(benzofuran-6-car bonyl)-5,7-dichloro-
1 ,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfbnyl)phenyl)propanoate
0
0
CI 0
CI 0
E 0 CI
0 CI
0 OH O.
O. ;S,, 0 0 0
0' k
-0 0
105201 To a stirred solution of lifitegrast (250 mg, 0.410 mmol) in anhydrous
DMF (5.0 mL) was
added 1-chloroethyl isopropyl carbonate (81.2 mg, 0.490 mmol) followed by
potassium carbonate
(73.0 mg, 0.530 mmol) and the mixture stirred at 55 C for 2 hours. The
mixture was diluted with
Et0Ac and washed successively with water followed by sat. brine solution. The
organic phase
was dried (MgSO4) and the solvent evaporated in vacuo . The residue was
dissolved in DMSO and
the product purified by reversed-phase preparative HPLC. Fractions containing
product were
combined and concentrated in vacuo to approximately 1/5 of the volume. The
mixture was diluted
with Et0Ac and washed successively with water followed by sat. brine solution.
The organic
phase was dried (MgSO4), filtered and the solvent evaporated in vacuo . The
residue was dissolved
in 1:1 MeCN-H20 and the solution frozen. The solvent was evaporated by
lyophilization to reveal
the title compound as an off-white solid (72.0 mg, 24%). LCMS (Method A): Rt =
7.87mins;
[M+H]+ = 745.3. 1-1-1-NMR (400 MHz, CD2C12) ö 7.78-7.91 (m, 2H), 7.76 (d, J=
2.1 Hz, 1H),
7.67 (d, J = 7.8 Hz, 1H), 7.57-7.64 (m, 2H), 7.49-7.56 (m, 1H), 7.31 (d, J=
7.8 Hz, 1H), 6.83-
6.93 (m, 1H), 6.77 (td, J= 11.1, 5.5 Hz, 1H), 6.32 (dd, J= 20.4, 8.5 Hz, 1H),
5.17-5.28 (m, 1H),
4.51-4.99(m, 3H), 3.78 (s, 2H), 3.17-3.49(m, 2H), 2.98-3.07(m, 3H), 2.87 (s,
2H), 1.49-1.56(m,
3H), 1.25-1.34 (m, 6H).
Chemical Synthesis Example 1-2:
105211 14(S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-
carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 543R)-1-oxido-1,2-
dithiolan-3-
yl)pentanoate and
14(S)-2-(2-(Benzofuran-6-carbony1)-5,7-dichloro-1,2, 3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5-
((3R)-2-oxido- 1 ,2-dithiolan-3-yl)pentanoate
-120-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0 0
O
CI 0 CI
0
0 CI 0 C I
0 0 0 0 0 0
0' 0'
o=s
o-
C I 0
0 CI
0-?-0 0
/
105221 1- [(2 S)-2- [ [2-(B enzofuran-6-carb ony1)-5,7-di chl oro-3 ,4-dihy
dro-1H-i soquinoline-6-
carb onyl] amino] -3 -(3 -methyl sul fonyl phenyl)prop anoyl J oxy ethyl
5-[(3R)-dithiolan-3-
yl]pentanoate (6.06 g) was dried in vctcuo (vac oven) for 4 days. Over this
time approximately
10% of the various sulfoxi de isomers had formed. The crude material was
purified by fl ash column
chromatography eluting with 8:2 isohexane-Et0Ac Et0Ac to yield 1-[(2S)-2-[[2-
(benzofuran-
6-carbony1)-5,7-dichloro-3 ,4-dihydro-1H-i soquinoline-6-carb onyl]amino] -3 -
(3 -
methyl sulfonylphenyl)propanoyl] oxy ethy 1 5- [(3R)-1-oxi dodithi olan-1-ium-
3 -yl]pentanoate (100
mg, 4%) as an off-white solid. LCMS (QC Method E): Rt = 2.63 min; 1M-F1-11+ =
863.3.
Chemical Synthesis Example 1-3:
105231 Step 1: 3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid
0 0
HOA`C111). HO(N)(
105241 To a stirred solution of (2R)-2-[acetyl(tert-butoxycarbonyl)amino]-3-
tritylsulfanyl-
propanoic acid (10.0 g, 21.6 mmol) in acetone (180 mL) was added in one
portion acetic anhydride
(4.00 mL, 43.1 mmol) and the reaction stirred at r.t. for 10 min. DBU (6.45
mL, 43.1 mmol) was
added in six portions over 2 mins and the reaction became a crimson red
colour. The reaction was
stirred at r.t. for 16 h. The reaction mixture was quenched onto water (200
mL), and extracted with
Et0Ac (2 x 200 mL). The combined organics were washed successively with water
(100 mL) and
-121-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
sat. brine solution (100 mL), dried (MgSO4), filtered and evaporated in vacuo.
The crude material
was purified by flash chromatography eluting with DCM
50% DCM-tert-butylmethyl ether.
Fractions containing product were combined and concentrated in vacuo followed
by
crystallisation from acetonitrile to yield 3-acety1-2,2-dimethylthiazolidine-4-
carboxylic acid (8.40
g, 77%) as a white crystalline solid. LCMS (QC Method E): Rt = 3.28 min; [M-H]
= 504.4. III-
NMR (400 MHz, CDC13) 6 7.36 (d, J= 7.3 Hz, 6H), 7.24-7.27 (m, 7H), 7.19 (dd,
J= 7.8, 5.5 Hz,
3H), 5.28 (q, J= 4.7 Hz, 1H), 2.68-2.80 (m, 2H), 2.47 (s, 3H), 1.38 (s, 9H).
[0525] Step 2: 1-Chloroethyl 3-acely1-2,2-dimethylthiazolidine-4-carboxylate
o CI 0
[0526] To a solution of 1-chloroethyl sulfochloridate (555 mg, 3.10 mmol) in
DCM (10 mL) was
added water (10 mL), (4R)-3-acetyl-2,2-dimethyl-thiazolidine-4-carboxylic acid
(450 mg, 2.21
mmol), tetrabutylammonium hydrogen sulfate (75.0 mg, 0.221 mmol) and NaHCO3
(744 mg, 8.86
mmol). The reaction mixture was stirred vigorously at room temperature for 18
h. The reaction
mixture was passed through a phase separator, evaporated onto silica and
purified by flash
chromatography eluting with isohexane ¨> 25% Et0Ac-isohexane. The fractions
containing
product were combined and concentrated in vacuo to yield 1-chloroethyl 3-
acety1-2,2-
dimethylthiazolidine-4-carboxylate (1.30 g, 58%). LCMS (QC Method E): Rt =
3.65 min;
[M+NH4r= 585.3.
[0527] Step 3:
1-WS)-2-(2-(Benzofiiran-6-carbony19-5,7-dichloro-1,2,3,4-
tetraliya'roisoquitioline-6-carboxamido)-3-(3-
(inethylsulfonyl)pheityl)propanoyl)oxy)ethyl 3-
acety1-2,2-dimethylthiazolidine-4-carboxylate
0
0 ci
0
CI 0
0 CI 0 CI
0 OH 0'
[0528] To a solution of Lifitegrast (100 mg, 0.162 mmol) in DMF (4.3 mL) was
added D1PEA
(106 L, 0.610 mmol) and 1 -chl oroethyl (4R)-3 -acetyl-2,2-di m ethyl -thi az
ol i di ne-4-carb oxyl ate
(54.0 mg, 0.200 mmol) and the reaction mixture was allowed to stir at 50 C
for 48 h. The reaction
-122-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
mixture was purified by flash chromatography eluting with isohexane Et0Ac to
yield 1-[(2S)-
2- [[2-(b enzofuran-6-carb ony1)-5, 7-di chl oro-3 ,4-di hy dro-1H-i s oquinol
ine-6-carb onyl ] amino]-3 -
(3 -methyl sulfonylphenyl)propanoyl] oxyethyl
(4R)-3-acety1-2,2-dimethyl-thiazolidine-4-
carboxylate (47.0 mg, 34%) as a pale-yellow solid. LCMS (QC Method E): Rt =
2.64 min;
[M+H]+ = 844.4.
Chemical Synthesis Example 1-4:
105291 Step 1: 3-((Allyloxy)carbony1)-2-methylthiazolidine-4-carboxylic acid
0 0
HOA,LE1 N1-
HON
105301 2-Methylthiazolidine-4-carboxylic acid (200 mg, 1.36 mmol) and NaHCO3
(350 mg, 4.17
mmol) were dissolved in THF (5.0 mL) and water (5.0 mL). Allylchloroformate
(220 p.L, 2.07
mmol) was added and the mixture stirred at r.t. for 16 h. The reaction mixture
was acidified to
pH2 with 1M HC1 and the solution extracted with Et0Ac (3 x 20 mL). The
combined organics
were dried (MgSO4), filtered and the solvent evaporated in vacito to yield 3-
((allyloxy)carbony1)-
2-methylthiazolidine-4-carboxylic acid (295 mg, 94%) as a colourless oil. LCMS
(QC Method
B)- Rt = 258 min; EM-Hr = 23O2
105311 Step 2: 3-Ally1 4-(1-chloroethyl) 2-methylthiazolidine-3,4-
dicarboxylate
o CI 0
HO.ILIN .11=IN
0
105321 3-((Allyloxy)carbony1)-2-methylthiazolidine-4-carboxylic acid (110 mg,
0.476 mmol),
tetrabutylammonium hydrogen sulfate (16.0 mg, 0.0476 mmol) and NaHCO3 (160 mg,
1.90
mmol) were dissolved in water (3.0 mL) and DCM (2.0 mL). 1-Chloroethyl
sulfochloridate (119
mg, 0.666 mmol) was added as a solution in DCM (1.0 mL) dropwise over 5 min at
r.t. The
reaction mixture was stirred at r.t. for 18h. The reaction mixture was diluted
with DCM and water.
The layers were separated and the organic layer washed with sat. NaHCO3(ao,
dried (MgSO4),
filtered and evaporated in vacuo to yield 3-ally1 4-(1-chloroethyl) 2-
methylthiazolidine-3,4-
dicarboxylate (66.0 mg, 47%) as a colourless oil. LCMS (QC Method B): Rt =
3.21 min; [M+H]
= 294.1.
105331 Step 3: 3-Ally1
4-(1-(((S)-2-(2-(benzgfuran-6-carbony1)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(inethylsullimyl)phenyl)propanoyl)oxy)ethyl) 2-
methylthiazolidine-3,4-dicarboxylate
-123-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
0 CI
0
CI 0
0 CI
- 0 CI os, o
c;Oç;s OOH 1 Ni
)-
10534] A mixture of Lifitegrast (70.0 mg, 0.114 mmol), 3-ally1 4-(1-
chloroethyl) 2-
methylthiazolidine-3,4-dicarboxylate (42.0 mg, 0.142 mmol), DIPEA (74.0 [IL,
0.426
mmol) and DMF (3.0 mL) was stirred under an atmosphere of nitrogen at 50 C
for 3 days. The
reaction mixture was diluted with Et0Ac (30 mL), washed sequentially with
water (30 mL), sat.
aqueous NaHCO3 (30 mL), water (30 mL) and sat. brine solution (30 mL), dried
(MgSO4), filtered
and the solvent evaporated in vacuo. The crude product was purified by flash
chromatography
eluting with isohexane
Et0Ac to yield 3-ally1 4-(1-(((S)-2-(2-(benzofuran-6-carbony1)-5,7-
di chl oro-1 ,2,3 ,4-tetrahy droi soquinol i ne-6-carb ox ami do)-3 -(3 -
(methy lsulfonyl)phenyl)propanoyl)oxy)ethyl) 2-methylthiazoli dine-3,4-di
carb oxyl ate as a
colourless oil (21.9 mg, 22%). LCMS (QC Method E): Rt = 2.88 min; [M+Hr =
872.3.
105351 Step 4:
1-(((S)-2-(2-(Benzofuran-6-carbony0-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carbox-amido)-3-(3-
(inethylsulfonyl)phenyl)propanoyl)oxy)ethyl 2-
me thylthiazolidine-4-carboxylate
0
0
ci 0 ci
0
1 0 CI 0 CI
CD %_,c)
-0 0
0/ ;S0 0 0 H
s/
105361 3-Ally1
4-(1-(((S)-2-(2-(b enzotiiran-6-carbonyl)-5,7-dichl oro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3 -(3 -
(methylsulfonyl)phenyl)propanoyl)oxy)ethyl) 2-
methylthiazolidine-3,4-dicarboxylate (21.9 mg, 0.0251 mmol) was dissolved in
DCM (1.1
mL). Phenylsilane (27 uL, 0.219 mmol) and tetraki
s(triphenylphosphine)palladium(0) (0.58 mg,
0.502 urnol) were then added and the reaction mixture stirred at r.t. for 15
min. The product was
purified by preparative reversed-phase HPLC and the appropriate fractions were
combined, frozen
(-78 C) and the solvent evaporated in vactto (lyophilisation) to yield 1-
(((S)-2-(2-(benzofuran-6-
carb ony1)-5, 7-di chl oro-1,2,3, 4-tetrahydroi soquinol ine-6-carb oxami do)-
3 -(3 -
-124-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 2-methylthiazolidine-4-carboxylate
(10.0 mg, 51%)
as a white solid. LCMS (QC Method E): Rt = 2.53 min; [M-41] = 790.3.
Chemical Synthesis Example 1-5:
105371 Step I. 2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethyl N-acetyl-S-trityl-
L-cysteinate
0 0
H \i HO " 0-)5'.Ny
105381 To a solution of Ac-Cys(Trt)-OH (1.00 g, 2.47 mmol) and tetraethylene
glycol (1.44 g,
7.40 mmol) in DCM (50 mL) was added 1-(3-dimethylaminopropy1)-3-ethyl-
carbodiimide
hydrochloride (473 mg, 2.47 mmol) and 4-(dimethylamino)pyridine (301 mg, 2.47
mmol). The
reaction mixture was stirred at r.t. for 20 h. The mixture was diluted with
DCM (100 mL), washed
sequentially with a mixture of 1M HCl (aq) (50 mL) and sat. brine solution (50
mL), then passed
through a phase separator. The solvent was evaporated in vacno and the crude
product purified by
flash column chromatography eluting with isohexane Et0Ac ¨> 10% Me0H-Et0Ac,
and then
further purified by flash column chromatography eluting with DCM 5% Me0H-DCM
to yield
2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl N-acetyl-S-trityl-L-cysteinate as
a colourless oil
(222 mg, 15%). LCMS (QC Method E): Rt = 2.64 min; [M-Pflr = 582.1.
105391 Step 2: 2-Chloro-4-oxo-3, 5,8,11, 14-pentaoxahexadecan-16-y1 N-acetyl-S-
tri tyl-L-
cysteinate
I I
n=3 0 n=3
0
105401 To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl (2R)-2-
acetamido-3-
tritylsulfanyl-propanoate (222 mg, 0.382 mmol) in DCM (5.0 mL) at 0 C was
added pyridine (62
[iL, 0.763 mmol) followed by 1-chloroethyl chloroformate (41 [iL, 0.382 mmol).
Stirring was
continued at 0 C. Additional portions of 1-chloroethyl chloroformate (41 ?IL,
0.382mm01) were
added after 4 h and 8 h. The reaction mixture was returned to it. and stirred
for a further 16 h. It
was then re-chilled to 0 C, a further portion of 1-chloroethyl chloroformate
(41 [IL, 0.38 mmol)
was added, then stirred for 3 h at this temperature. The reaction mixture was
partitioned between
-125-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
DCM (30 mL) and water (30 mL) and passed through a phase separator. The
solvent was
evaporated in memo and the crude product purified by flash column
chromatography eluting with
DCM
5% Me0H-DCM to yield 2-chloro-4-oxo-3,5,8,11,14-pentaoxahexadecan-16-
y1 N-
acetyl-S-trityl-L-cysteinate as a colourless oil (177 mg, 67%). LCMS (QC
Method E): Rt = 3.11
min; [M+H]+ = 688.1.
[0541] Step 3: (3,S)-1-(2-(13enzoficran-6-carbony1)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinolin-6-
y1)-6-methyl-3-(3-(methylsulfony)benzyl)-1,4,8-trioxo-5,7,9,12,15,18-hexaora-2-
azaicosan-20-
y1 N-acetyl-S-tritylcysteinate
ci
0
0
CI 0 E 0 CI
0 -
0
0 CI 0/
N
n=3
0
0 OH
0/
105421 A mixture of Lifitegrast (60 mg, 0.0975
mmol), 2-[2-[2-[2-(1-
chloroethoxycarbonyloxy)ethoxy] ethoxy] ethoxy ] ethyl
(2R)-2-acetami do-3 -trityl sul fanyl-
propanoate (81 mg, 0.117 mmol), DIPEA (34 uL, 0.195 mmol) and DMF (3.0 mL) was
stirred
under an atmosphere of nitrogen at 50 C for 24 h, then for a further 4 days
at r.t., then for a further
24 h at 50 C. The reaction mixture was diluted with Et0Ac (40 mL), washed
sequentially with
saturated aqueous NaHCO3 (40 mL), water (40 mL) and sat. brine solution (40
mL), then dried
(MgSO4). The solvent was evaporated in vacuo and the crude product purified by
flash column
chromatography eluting with isohexane
Et0Ac ¨> 10% Me0H-Et0Ac to yield (3S)-1-(2-
(benzofuran-6-carbony1)-5,7-dichloro-1,2,3,4-tetrahydroi soquinol n-6-y1)-6-m
ethy1-3 -(3 -
(methyl sulfonyl)b enzy1)-1,4, 8-tri oxo-5,7,9,12,15,18-hexaoxa-2-azai cosan-
20-y1 N-acetyl- S -
tritylcysteinate as a colourless oil (68.3 mg, 53%). LCMS (QC Method E): Rt =
3.15 min;
[M-FI-1]+ = 1266.5.
105431 Step 4: (3S)-1-(2-(Benzqfuran-6-carbony1)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinolin-6-
yl)-6-methyl-3-(3-(methylsulfonyl)benzyl)-1,4,8-trioxo-5,7,9,12-tetraoxa-2-
azatetradecan-14-y1
acetyl-L-cysteinate
-126-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
a 0
0
0 CI H CI
0
0 0 0 0 0 CI
INLO
-.0 0 0.3'S 0 0 0 0 14
n=3
0
HS
105441 To a solution
of 1-[2-[2-[2-[2-[(2R)-2-acetami do-3 -trityl sul fanyl -
prop anoyl] oxy ethoxy] ethoxy ethoxy] ethoxy carb onyl oxy] ethyl
(2 S)-2- [ [2 -(b enzofuran-6-
carb ony1)-5,7-di chl oro-3,4-dihydro-1H-i soquinoline-6-carb onyl] amino]-3-
(3-
methylsulfonylphenyl)propanoate (65 mg, 0.0515 mmol) in DCM (2.0 mL) was
added triethylsilane (41.2 p.L, 0.258 mmol) followed by a solution of 10% TFA-
DCM (2.0 mL).
The mixture was stirred at r.t. for 30 min, partitioned between DCM (10 mL)
and saturated
aqueous NaHCO3 (10 mL) then passed through a phase separator. The solvent was
evaporated in
vacuo and the crude product purified by preparative reverse-phase HPLC.
Desired fractions were
combined, and the solvent evaporated in vacuo . The residue was dissolved in
1:1 MeCN-H20 (3.0
mL) and the solvent frozen (-78 C), then evaporated in vacuo (lyophilisation)
to yield (3S)-1-(2-
(b enzofuran-6-carbonyl)-5, 7-di chl oro-1,2,3,4-tetrahy droi soquinol i n-6-
y1)-6-m ethy1-3 -(3-
(methylsul fonyl)b enzy1)-1,4, 8-tri oxo-5, 7,9,12-tetraoxa-2-azatetradecan-14-
y1 acetyl-L-cysteinate
as a white solid (22.5 mg, 43%). LCMS (QC Method E): Rt = 2.52 min; [M+H] =
1024.2.
105451 The following compound was synthesized via an analogous method:
Structure Analytical data
c 0
LCMS (QC Method E):
0
Rt = 2.50 min; [M-F1-1] = 1200.4
0.,,,sõ 0 0 _ 0
0,
n=7 0
HS
-127-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Chemical Synthesis Example 1-6:
105461 Step I: N-Acetyl-N-(tert-butoxycarbony1)-S-trityl-L-cysteine
0 H 0 Oy-
HO)LX N HO)Lf N y0OIO
l<
0 0
105471 To a solution of N-Boc-S-trityl-L-cysteine (1.00 g, 2.16 mmol) and
D1PEA (2.25 mL, 12.9
mmol) in acetone (50 mL) was added acetyl chloride (1.0 mL 12.9 mmol). The
reaction mixture
was stirred at r.t. for 6 h then quenched with water (50 mL) and stirred at
r.t. for 30 min. The layers
were separated, and the organic phase dried (MgSO4) and filtered. The solvent
was evaporated in
vac/10 and the crude product purified by flash column chromatography eluting
with isohexane
Et0Ac to yield 1-chloroethyl N-acetyl-N-(tert-butoxycarbony1)-S-trityl-L-
cysteine as a yellow
foamy solid (885 mg, 81%). LCMS (QC Method D): Rt = 2.24 min; EM-1-1]- =
504.2.
105481 Step 2: 1-Chloroethyl N-acetyl-N-(tert-butoxycarbony1)-S-trityl-L-
cysteinate
0 CI 0
HO N Noc/ 00
-jir
0 0
S
105491 To a solution of N-acetyl-N-(tert-butoxycarbony1)-S-trityl-L-cysteine
(885 mg, 1.75
mmol) and 1-chloroethanesulfonyl chloride (440 mg, 2.45 mmol) in DCM (20 mL)
was added a
solution of tetrabutylammonium hydrogen sulfate (60 mg, 0.175 mmol) and NaHCO3
(588 mg,
7.00 mmol) in water (20 mL). The reaction mixture was stirred vigorously at
r.t. overnight then
passed through a phase separator. The solvent was evaporated in wren and the
crude product
purified by flash column chromatography eluting with isohexane ¨> 25% Et0Ac-
isohexane to
yield 1-chloroethyl N-acetyl-N-(tert-butoxycarbony1)-S-trityl-L-cysteinate as
a colourless oil (620
mg, 62%). LCMS (QC Method E): Rt = 3.82 min; [M+Na] = 590.2
105501 Step 3: 1-((N-Acetyl-N-(tert-butoxycarbony1)-S-trityl-L-
cysteinyl)oxy)ethyl (25)-2-(2-
(benzefurctn-6-carbonyl)-5,7-dichlore-1,2,3,4-tetrcthydroisoquinoline-6-
earboxamido)-3-(3-
(tnethylsulfonAphenyOpropanoate
-128-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0
CI
0
0
CI 0 _ 0 CI
Ck'S, 0 0 0
= 0 CI
===-= 0
0 OH S)
105511 A mixture of Lifitegrast (200 mg, 0.325 mmol), 1-chloroethyl N-acetyl-N-
(tert-
butoxycarbony1)-S-trityl-L-cysteinate (222 mg, 0.390 mmol), DIPEA (113 ILLL,
0.650 mmol)
and DMF (3.0 mL) was stirred under an atmosphere of nitrogen at 50 C for 42
h. The reaction
mixture was diluted with Et0Ac (40 mL), washed sequentially with saturated
aqueous
NaHCO3 (40 mL), water (40 mL) and sat. brine solution (40 mL), then dried
(MgSO4) and filtered.
The solvent was evaporated in -vacuo and the crude product purified by flash
column
chromatography eluting with i soh ex an e
Et0 A c. The fractions containing product were
combined and the solvent evaporated in vacuo to yield 1-((N-acetyl-N-(tert-
butoxycarbony1)-S-
trityl-L-cy steinyl)oxy)ethyl
(2 S)-2-(2-(b enzofuran-6-carbonyl)-5,7-dichl oro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate
as a colourless
oil (29 mg, 8%). LCMS (QC Method E): Rt = 3.51 min; [M+H] = 1163.5.
105521 Step 4: 1-((Acetyl-L-cysteinyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-
carbonyl)-5,7-dichloro-
1,2,3,4-letrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoate
0
HJNQ
CI 0
0
CI N
11101 _ 0 CI
50
CL'S 0 0 0
0 CI
0
0
0
H S
105531 To a solution of 1-((N-acetyl-N-(tert-butoxycarbony1)-S-trityl-L-
cysteinyl)oxy)ethyl
(2 S)-2-(2-(b enzofuran-6-carbony1)-5,7-dichl oro-1,2,3 ,4-tetrahy droi so qui
nol i ne-6-c arb oxami do)-
3-(3-(methylsulfonyl)phenyl)propanoate (25 mg, 0.0218 mmol) in DCM (2.0 mL) at
0 C was
-129-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
added triethylsilane (0.2 L, 0.013 mmol) followed by a 5% solution of TFA-DCM
(2.0 mL) and
the reaction stirred at r.t. for 16 h. The solvent was evaporated in vacua and
the crude product
purified by preparative reversed-phase HPLC. The desired fractions were
combined, frozen (-78
cC), and the solvent evaporated in vacua (lyophilisation) to yield 1-((acetyl-
L-cysteinyl)oxy)ethyl
(2S)-2-(2-(benzofuran-6-carbony1)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-
6-carboxamido)-
3-(3-(methylsulfonyl)phenyl)propanoate as a white solid (8.2 mg, 47%). LCMS
(QC Method A):
Rt = 7.54 min; [M+HF = 804.4. 'H-NMR (400 MHz, DMSO-d6) 6 9.17-9.22 (1H, m),
8.35-8.37
(1H, m), 8.11-8.14 (1H, m), 7.87 (1H, br s), 7.66-7.79 (4H, m), 7.30-7.59 (3H,
m), 7.04 (1H, m),
6.81 (1H, m), 4.82-4.88 (1H, m), 4.72 (2H, br s), 4.35-4.49 (1H, m), 3.64-3.88
(2H, br m), 3.27
(1H, m), 3.13-3.15 (3H, m), 2.96-3.08 (1H, m), 2.55-2.88 (5H, m), 1.87-1.88
(3H, m), 1.40-1.49
(3H, m).
Chemical Synthesis Example 1-7:
105541 Step 1: N-Acetyl-S-(pyridin-2-ylthio)-L-cysteine
SH
0 Xi(
OH _____________________________________________________________ S '.µ1\1
A
0
"AN
0 fy
OH
0
105551 To a solution of N-acetyl-L-cysteine (400 mg, 2.45 mmol) in water (3.4
mL) at r.t. was
added a solution of 2,2'-dipyridyl disulfide (1080 mg, 4.90 mmol) in methanol
(3.4 mL), resulting
in a bright yellow solution. Stirring was continued at r.t. for 16 h. The
solvent was evaporated in
vacua to yield a thick yellow oil. This was suspended in water (30 mL) and
extracted with DCM
(3 x 30 mL). The combined organics were washed with sat. brine solution (30
mL), dried (Na2SO4)
and filtered. The solvent was evaporated in vacua and the crude product
purified by flash column
chromatography eluting with DCM 15% Me0H-DCM to yield N-acetyl-S-(pyridin-2-
ylthio)-
L-cysteine as a white solid (161 mg, 24%). LCMS (QC Method E): Rt = 1.60 min;
[M-FH]+ =
273.1.
105561 Step 2: S4(2R)-2-acetamido-3-(1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-
dichloro-
1 , 2 , 3 ,4-tetrahydroisoquinohne-6-carboxamido)-3-( 3-
(inethylsidfonyl)phenyl)propanoyDoxy)ethoxy)-3-oxopropyl)thio)-AT-acetyl-L-
cysteine
-130-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
N
0
0
11 0
CI
/
CI
0 0 0 CI
= 0 CI O'S
_L0)LAL.-
0
o 0
HS
)1.4' N OH
Hv- Y
0
105571 To a solution of 1-((acetyl-L-cysteinyl)oxy)ethyl (2S)-2-(2-(b
enzofuran-6-carb ony1)-5,7-
di chloro-1,2,3 ,4-tetrahydroi soquinoline-6-carb oxami do)-3 -(3 -
(methylsulfonyl)phenyl)propanoate (5.0 mg, 0.00621 mmol) in chloroform (1.0
mL) at r.t was
added a solution of N-acetyl-S-(pyridin-2-ylthio)-L-cysteine (3.4 mg, 0.0124
mmol) in
chloroform (1.0 mL) and triethylamine (1.7 uL, 0.0124 mmol). Stirring was
continued at r.t. for 2
h. The solvent was evaporated in vacuo and the crude product purified by
preparative reverse-
phase HPLC. The desired fractions were combined, frozen (-78 C), and the
solvent evaporated in
vacno (ly ophili sati on) to yield S-(((2R)-2-acetamido-3-(1-(((S)-2-(2-(b
enzofuran-6-carb ony1)-
5, 7-dichloro-1,2,3 ,4-tetrahydroi soquinoline-6-carb oxamido)-3 -(3-
(methyl sulfonyl)phenyl)propanoyl)oxy)ethoxy)-3 -oxopropyl)thio)-N-acetyl-L-
cysteine as a
white solid (1.5 mg, 25%). LCMS (QC Method E): Rt = 2.35 min; [M+F-1]+ =
965.5.
105581 Step 3:
1-WS)-2-(2-(benzofitran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(inethylsulfonyl)phenyl)propanoy0oxy)ethyl S-
(((2R)-2-acetamido-3-(1-(((S)-2-(2-(benzofitran-6-carbonyl)-5,7-dichloro-
1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(inethylsulfonyOphenyl)propanoyl)oxy)ethoxy)-3-
oxopropyl)thio)-N-acetyl-L-cysteinate
CI
=
0,
0 0 0ci
CI
05S,_ NI(
-'1"*0-j1)'=
0'
So 0/
0
A
.===, 0 C I
0 0 0 õ 0
0,s,o
o' AN'c Y-
--s=0
HS
0
0
0 0 0
CI
/
0 101
CI
0
-131-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
105591 To a colourless solution of 1-((acetyl-L-cysteinyl)oxy)ethyl (2S)-2-(2-
(benzofuran-6-
carb ony1)-5, 7-di chl oro-1,2,3 ,4-tetrahydroi soquinol ine-6-carb oxami do)-
3 -(3 -
(methylsulfonyl)phenyl)propanoate (5.0 mg, 0.00621 mmol), sodium acetate (1.0
mg, 0.0124
mmol), THE (1.0 mL) and water (0.50 mL) at r.t. was added a solution of iodine
(0.79 mg,
0.00311 mmol) in TI-IF (0.10 mL). Stirring was continued at r.t. for 20 min.
The reaction mixture
was diluted with Et0Ac (15 mL) and water (5 mL). Saturated aqueous sodium
thiosulfate was
then added until the solution became colourless. The organic phase was washed
with sat. brine
solution (10 mL), dried (MgSO4) and filtered. The solvent was evaporated in
yam and the crude
product purified by preparative reverse-phase FIPLC. The desired fractions
were combined, frozen
(-78 SC), and the solvent evaporated in vacuo (lyophilisation) to yield 1-
(((S)-2-(2-(benzofuran-6-
carb ony1)-5, 7-di chl oro-1,2,3 ,4-tetrahy droi s o qui nol i n e-6-c arb
oxami do)-3 -(3 -
(methyl sul fonyl)ph enyl )prop an oyl )oxy)ethyl S-(02R)-2-acetami do-3 -(1-
(((S)-2-(2-(b en zofuran-
6-carb ony1)-5 ,7-dichloro-1,2,3,4-tetrahydroi soquinol ine-6-carb oxamido)-3 -
(3 -
(methylsulfonyl)phenyl)propanoyl)oxy)ethoxy)-3 -oxopropyl)thio)-N-acetyl-L-
cysteinate as a
white solid (1.5 mg, 15%). LCMS (QC Method E): Rt = 2.72 min; [M+H] = 1607.7.
Chemical Synthesis Example 1-8:
105601 1-(2-(Acelylthio)acetoxy)ethyl (2,9-2-(2-(benzofuran-6-carbonyl)-5,7-
dichloro-1,2,3,4-
ietrahydroisoquinoline-6-carboxamido)-3-(3-nnethylsulfonyOphenyl)propanoate
0
O
0
CI çOO CI
0
0 0
0 0
_ 0 c,
,
0 0 0 0 0 0
0/
11
105611 To a stirred solution of triphenylphosphine (91 mg, 0.348 mmol) in
anhydrous TTIF (3.0
mL) at 0 C under an atmosphere of nitrogen was added diisopropyl
azodicarboxylate (69 tiL,
0.348 mmol) and the resulting yellow mixture was stirred at 0 C for 30 min.
To the reaction was
added dropwise a solution of 1-(2-hydroxyacetyl)oxyethyl (2S)-2-[[2-
(benzofuran-6-carbony1)-
5,7-dichloro-3,4-dihydro-1H-i soquinoline-6-carb onyl] amino] -3 -(3 -
methylsulfonylphenyl)propanoate (100 mg, 0.139 mmol) and thioacetic acid (18
iLtL, 0.251 mmol)
in anhydrous TI-IF (2.0 mL) and the stirred at r.t. for 16 h. The reaction was
diluted with Et0Ac
(2 x 30 mL) and water and the layers separated. The organic phase was washed
with water (20
mL) and the combined aqueous layers were extracted with Et0Ac (20 mL). The
combined
-132-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
organics were washed with sat. brine solution (20 mL), dried (MgSO4), filtered
and concentrated
in vacuo. The crude product was purified by flash chromatography eluting with
isohexane
Et0Ac. Fractions containing product were combined and concentrated in vacuo to
give the desired
product still containing impurities. The product was purified by preparative
reversed-phase HPLC
and the appropriate fractions were combined and the solution frozen (-78 C).
The solvent was
evaporated in vacuo (lyophilisation) to yield 1-(2-
acetylsulfanylacetyl)oxyethyl (2S)-2-[[2-
(benzofuran-6-carbony1)-5,7-di chl oro-3,4-dihydro-1H-i soquinoline-6-carbonyl
]amino]-3-(3-
methylsulfonylphenyl)propanoate (9.0 mg, g%) as a white solid. LCMS (QC Method
C.): Rt =
7.72 min; [M+H]P = 775.4.
Chemical Synthesis Example 1-9:
105621 2-1-1ydroxyethyl (S)-2-(2-(henzofuran-6-carhony1)-
5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-ccirboxamido)-3-(3-(inethylsidfonyl)phenyl)propanoate
0
ci 0 ci
0
101 0 CI 111101
E 0 01
0.
0 OH
0' 0 OH
105631 Lifitegrast (250 mg, 0.406 mmol), ethylene glycol (32 pL, 0.579 mmol),
1-(3-
dimethylaminopropy1)-3-ethyl-carbodiimide hydrochloride (III mg, 0.579 mmol)
and DMAP
(9.4 mg, 0.0772 mmol) were dissolved in DCM (10 mL) and the mixture stirred at
r.t. for 40 h.
The reaction mixture was diluted with DCM (40 mL) and washed with H70 (50 mL).
The solution
was passed through a phase separator and the filtrate evaporated in vacuo to
¨5 mL volume. The
crude product was purified by flash chromatography (Biotage Si-SFAR; 25 g)
eluting with DCM
¨> 9:1 DCM-Me0H. The isolated material was further purified by flash
chromatography (Biotage
Si-SFAR; 25 g) eluting 1:1 isohexane-Et0Ac Et0Ac. The isolated material was
further purified
by flash chromatography (Biotage SFAR KP-Amino D; 28 g) eluting with DCM 95:5
DCM-
Me0H. The isolated material was further purified by flash chromatography
(Biotage SFAR KP-
Amino D; 28 g) eluting with DCM ¨> 98:2 DCM-Me0H. The product was dissolved in
1:1
MeCN-H20 (6 mL) and the solution frozen (-78 C), the solvent was evaporated
in vacuo
(lyophilization) to yield the title compound as a white solid (52.7 mg, 21%).
LCMS (Method E):
Rt = 2.21 min; [M-FH]+ = 659.1.
-133-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Chemical Synthesis Example 1-10:
105641 3-Hydroxypropyl
(S)-2-(2-(benzofitran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate
O
CI 0
N
O.
0 0
0/ OH
105651 The title compound was synthesized via an analogous method to the
method described in
Chemical Synthesis Example 1-9. The title compound was afforded as a white
solid (90.5 mg,
35%). LCMS (Method E): Rt = 2.24 min; [M+Hr = 673.
Chemical Synthesis Example I-11:
105661 2-(((S)-2-(2-(Benzofifran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-
carboxamido)-3-(3-(methylsulfony1)phenyl)propanoyl)oxy)ethyl
5-((R)-1,2-dithiolan-3-
yl)pentanoate
0
=
0
ci
0
ci 0
0 CI ____________________________________________ 71, 11101 0 CI
(: 0 0 0 0 '
0'
0
105671 A mixture of 2-hydroxyethyl (S)-2-(2-(benzofuran-6-carbony1)-5,7-
dichloro-1,2,3,4-
tetrahydroi soquinoline-6-carboxami do)-3 -(3 -(m ethyl
sulfonyl)phenyl)propanoate (40 mg,
0.0606 mmol), lipoic acid (13 mg, 0.0606 mmol), 1-(3-dimethylaminopropy1)-3-
ethyl-
carbodiimide hydrochloride (17 mg, 0.0910 mmol) and DMAP (1.5 mg, 0.0121 mmol)
were
dissolved in DMF (2.0 mL) and the mixture stirred at r.t. for 96 h then stored
at 5 C for 24 days.
Lipoic acid (6.2 mg, 0.0301 mmol), 1-(3-dimethylaminopropy1)-3-ethyl-
carbodiimide
hydrochloride (5.8 mg, 0.0303 mmol) and DMAP (1.5 mg, 0.0123 mmol) were added
and the
reaction mixture stirred at r.t. for 120 h. The reaction mixture was filtered,
and the crude product
purified by preparative reversed-phase HPLC. Fractions containing desired
product were
combined and the solution frozen (-78 C). The solvent was evaporated in vacuo
(lyophilization)
to yield the title compound as a white solid (20.6 mg, 40%). LCMS (Method F):
Rt = 5.06 min;
[M+H] = 847Ø
-134-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
Chemical Synthesis Example 142:
[0568] 3-(((S)-2-(2-(Benzoficran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoqinnohne-6-
carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)propyl 5-((R)-
1,2-dithiolan-3-
yl)pentanoate
0
CI 0
110 0 CI
0 0 0
0'
[0569] The title compound was synthesized via an analogous method to the
method described in
Chemical Synthesis Example I-11. The title compound was afforded as an off-
white solid (113
mg, 22%). LCMS (Method E): Rt = 3.00 min; [M+H] = 861.2.
Chemical Synthesis Example 1-13:
[0570] Step 1: Chloromethyl (R)-5-(1,2-dithiolan-3-yl)pentanoate
0 0
HO
CI
[0571] Lipoic acid (400 mg, 1.94 mmol), chloromethyl chlorosulfate (0.270 mL,
2.66
mmol), sodium bicarbonate (638 mg, 7.60 mmol) and tetrabutylammonium hydrogen
sulfate (65
mg, 0.191 mmol) were dissolved in 1:1 DCM-H20 (20 mL) and the mixture stirred
vigorously at
r.t. for 20 h. The reaction mixture was passed through a phase separator and
the filtrate washed
with sat. NaHCO3(ao (10 mL). The organic phase was dried (MgSO4), filtered and
the solvent
evaporated in vacuo to yield the title compound as a yellow oil that turned
into a gum after standing
at r.t. (221 mg, 43%). The material was used in the next step without further
purification.
[0572] Step 2: (((S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinohne-
6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)methyl 5-((R)-
1,2-dithiolan-3-
yl)pentanoate
0
0 ci
0
CI 0
401 N
0 CI
0 CI
C:1Sõ, 0 0 0
OOH 0'
0'
-135-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0573] Lifitegrast (60.0 mg, 0.0975 mmol) and chloromethyl (1)-5-0,2-dithiolan-
3-ylVentanoate
(28 mg, 0.111 mmol) were dissolved in DMF (2.0 mL). DIPEA (30 [iIõ 0.172 mmol)
was added
and the mixture stirred at r.t. under N2 for 40 h. The reaction mixture was
stored at 5 "V for 24
days. Chloromethyl (R)-5-(1,2-dithiolan-3-yl)pentanoate (28.3 mg, 0.111 mol)
was added and the
reaction mixture stirred at 50 C for 5 days. The reaction mixture was
filtered and the crude
product purified by preparative reversed-phase IIPLC. Desired fractions were
combined and the
solution frozen (-78 C). The solvent was evaporated in vacuo (lyophilization)
to yield the title
compound as a white solid (10.0 mg, 13%). LCMS (Method F): Rt = 5.10 min;
[M+Hr = 833Ø
Chemical Synthesis Example 1-14:
[0574] Step 1: 1-Chloroethyl ethyl succinate
0 0
HO
CI
0 0
105751 A mixture of mono-ethyl succinate (200 mg, 1.37 mmol), 1-chloroethyl
sulfochloridate
(0.21 mL, 1.92 mmol), sodium bicarbonate (460 mg, 5.47 mmol) and
tetrabutylammonium
hydrogen sulfate (47 mg, 0.137 mmol) were dissolved in 1:1 DCM-H20 (10 mL) and
the mixture
stirred vigorously at r.t. for 18 h. The solution was passed through a phase
separator and the filtrate
evaporated in vacuo. The crude product was purified by flash chromatography
(Biotage SFAR
cartridge; 10 g) eluting with isohexane ¨> 8:2 isohexane-Et0Ac to yield the
title compound as a
colorless oil (130 mg, 46%). rt he material was used in the next step without
further purification.
[0576] Step 2: 1-(((S)-2-(2-(Benzofuran-6-carbonyl)-
5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(nethylsulfonyl)phenyl)propanoyl)oxy)ethyl ethyl
succinate
0
0 CI
0
CI 0
0 ci
101 0 c,
0 0
o--s 0 OH
0// 0
0
[0577] Lifitegrast (150 mg, 0.244 mmol) and 1-chloroethyl ethyl succinate (58
mg, 0.278 mmol)
were dissolved in DMF (2.0 mL). DIPEA (81 [IL, 0.465 mmol) was added and the
mixture stirred
at r.t under 1\17 for 120 h. The reaction mixture was filtered, and the crude
product purified by
preparative reversed-phase HPLC. Desired fractions were combined and the
solution frozen (-78
-136-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
C). The solvent was evaporated in vacuo (lyophilisation) to yield the title
compound as a white
solid (30.5 mg, 17%). LCMS (Method F): Rt = 4.96 min; [M-F1-1] = 787Ø
Chemical Synthesis Example 1-15:
105781 Step I. A mixture of chloromethyl 54(3R)-2-oxido-I,2-dithiolan-3-
yl)pentanoate and
chloromethyl 5-((3R)-1-oxido-1,2-dithiolcm-3-yl)pentanoate
0
CI
HO=CS),-0
0
CI 0
105791 To a stirred mixture of diastereoisomers of 5-((3R)-2-oxido-1,2-
dithiolan-3-yl)pentanoic
acid and 5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoic acid (300 mg, 1.35 mmol)
in 1:1 DCM-
H20 (20 mL) was added chloromethyl chlorosulfate (0.20 mL, 2.02 mmol), sodium
bicarbonate
(453 mg, 5.40 mmol) and tetrabutylammonium hydrogen sulfate (46 mg, 0.135
mmol). The
reaction mixture was stirred vigorously at r.t. for 18 h. The reaction mixture
was passed through
a phase separator and the filtrate evaporated in vacuo to yield a mixture of
the title compounds as
a yellow oil (306 mg, 84%). The material was used in the next step without
further purification.
[0580] Step 2: A mixture of (((S)-2-(2-(henzofuran-6-carbony1)-5,7-thchloro- I
,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylswIfonyl)phenyl)propanoyl)oxy)rnethyl 5-
((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and (((S)-2-(2-(benzofuran-6-
carbony1)-5,7-
dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoyl)oxy)methyl 5-((3R)-1-oxido-1,2-dithiolan-3-
yl)pentanoate;
and a mixture of (((S)-2-(2-(benzgfUran-6-carbony1)-
5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsittfonyl)phenyl)propanoyl)oxy)methyl 5-
((R)-2,2-dioxido-1,2-dithiolan-3-Apentanoate and (((S)-2-(2-(benzofuran-6-
carbonyl)-5,7-
dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyOpheny0propanoy0oxy)metkvl 5-((R)-1,1-dioxido-1,2-dithiolan-3-
yl)pentanoate
-137-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
CI
=
C)/
0 CI 11101 0 CI
(00 0.
0 0 0
CI
0/
1101
0 CI
0S.= 0 OH 0
0
CI CI
H N Ig6 N N
()/
o o o 0S c"--. o
0 0'
0 -uw-Cst
105811 A mixture of Lifitegrast (100 mg, 0.162 mmol), chloromethyl 5-((3R)-2-
oxido-1,2-
dithi ol an-3 -yl)p entanoate and chl orom ethyl 5 -((3R)-1-oxi do-1,2-dithi
ol an-3 -yl)p entan pate (50
mg, 0.185 mmol) were dissolved in DMF (2.0 mL). DIPEA (54 p.L, 0.302 mmol) was
added and
the mixture stirred at 50 C under N2 for 42 h. The reaction mixture was
filtered, and the crude
product purified by preparative reversed-phase HPLC. Fractions containing
desired product were
combined and the solution frozen (-78 C). The solvent was evaporated in vacuo
(lyophilization)
to yield two products:
105821 Product 1: A mixture of diastereoisomers of (((S)-2-(2-(benzofuran-6-
carbony1)-5,7-
di chl oro-1,2,3 ,4-tetrahy droi soquinoli ne-6-carb ox ami do)-3 -(3 -
(methyl sulfonyl)phenyl)propanoyl)oxy)methyl
5 -((3R)-2-oxi do-1,2-dithi ol an-3 -yl)p entanoate
and
(((S)-2-(2-(b enzofuran-6-carb ony1)-5, 7-di chl oro-1,2,3 ,4-tetrahy
droi s oquinoline-6-
carb oxami do)-3 -(3 -(methyl sulfonyl)phenyl)propanoyl)oxy)methyl
5-((3R)-1-oxi do-1,2-
dithiolan-3-yl)pentanoate as a white solid (11.5 mg, 9%). LCMS (Method F): Rt
= 5.73 min;
[M+H] = 849Ø
105831 Product 2: A mixture of (((S)-2-(2-(benzofuran-6-carbony1)-5,7-dichloro-
1,2,3,4-
tetrahydroi soquinoline-6-carb oxami do)-3 -(3 -(methyl
sulfonyl)phenyl)propanoyl)oxy)methyl 5-
((R)-2,2-di oxi d o-1,2-dithi ol an-3 -yl)p entanoate
and (((S)-2-(2-(b enzofuran-6-carb ony1)-5, 7-
di chl oro-1,2,3 ,4-tetrahy droi soquinoli ne-6-carb ox ami do)-3 -(3 -
(methyl sulfonyl)phenyl)propanoyl)oxy)methyl 5 -((R)-1,1-di oxido-1,2-dithi
olan-3 -yl)pentanoate
as a white solid (25.0 mg, 19%) LCMS (Method F): Rt = 5.99 min; [M+H] = 864.9.
Chemical Synthesis Example 1-16:
105841 Step 1: 1-Chloroethyl (3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)
carbonate
0
HOOCCI LO).(00 0
-138-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
105851 To a stirred solution of 3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol
(587 mg, 3.66
mmol) (prepared according to the procedure reported in W02016/77832) in DCM
(20 mL) at 0
C was added pyridine (593 [IL, 7.33 mmol) and 1-chloroethyl chloroformate (395
[IL, 3.66
mmol). The reaction mixture was gradually warmed to r.t., with continual
stirring for 16 h. The
solution was washed with H20 (20 mL), passed through a phase separator and the
filtrate
evaporated in vacuo. The crude product was purified by flash chromatography
(Biotage Si-SFAR;
50 g) eluting with isohexane 1:1 isohexane-Et0Ac to yield the title
compound as a colorless
oil (702 mg, 72%). -41-NMR (400 MHz, CDC13) 6 641 (q, J= 5.8 Hz, 1H), 4_53-
4.63 (m, 1H),
4.26-4.39 (m, 2H), 3.76-3.89 (m, 2H), 3.42-3.55 (m, 2H), 1.92-2.06 (m, 2H),
1.81 (d, J= 6.0 Hz,
3H), 1.44-1.80 (m, 6H).
105861 Step 2: 1 -(((3-((Tetrahydro-2H-pyran-2-
yl)oxy)propoxy)carbonyl)oxy)ethyl (25)-2-(2-
(benzgfuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-
carboxamido)-3-(3-
(methylsidfonyOpheny0propanoate
ci
ci 0
0 CI
1110
0 CI
O.
;S
0 OH
;Sõ 0 0 0 õ
0' k
105871 A mixture of Lifitegrast (150 mg, 0.244 mmol) and 1-chloroethyl (3-
((tetrahydro-2H-
pyran-2-yl)oxy)propyl) carbonate (74 mg, 0.278 mmol) were dissolved in DMF
(2.0 mL). DIPEA
(81 !IL, 0.465 mmol) was added and the mixture stirred at 50 C under N2 for
144 h. The reaction
mixture was diluted with water (20 mL), extracted with Et0Ac (20 mL) and then
washed
successively with sat. NaHCO3(aco (20 mL), water (20 mL) and sat. brine
solution (20 mL). The
organic phase was dried (MgSO4), filtered and evaporated in vacuo to yield the
title compound as
a yellow oil (114 mg, 58%). LCMS (Method G): Rt = 1.88 min; [M+NH4] = 862.2.
Chemical Synthesis Example 1-17:
105881 Step 1: 1-Chloroethyl (2-((tetrahydro-2H-pyran-2-yOory)ethyl) carbonate
CI 0 0
105891 1-Chloroethyl (2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl) carbonate was
synthesized via an
analogous method to the method described in step 1 of preparing 1-chloroethyl
(3-((tetrahydro-
2H-pyran-2-yl)oxy)propyl) carbonate in Chemical Synthesis Example 1-16. 1-
Chloroethyl (2-
((tetrahydro-2H-pyran-2-yl)oxy)ethyl) carbonate was afforded as a colorless
oil (321 mg, 74%).
-139-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
1H-NMR (400 MHz, CDC13) 6 6.42 (q, J = 5.8 Hz, 1H), 4.58-4.69 (m, 1H), 4.29-
4.47 (m, 2H),
3.88-4.00 (m, 1H), 3.78-3.88 (m, 1H), 3.59-3.73 (m, 1H), 3.45-3.56 (m, 1H),
1.82 (d, J= 6.0 Hz,
3H), 1.80-1.45 (m, 6H).
105901 Step 2: 1-(((24(Tetrahydro-2H-pyran-2-yboxy)ethoxy)carbonyl)oxy)ethyl
(2S)-2-(2-
(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-
carboxamido)-3-(3-
(inethylsulfbnyl)phenyl)propanoate
O
CI 0
N
0 CI
=====-
0 0 0
0/' I A
0 0
105911 The title compound was synthesized via an analogous method to the
method described in
step 1 of preparing 1-(((3-((Tetrahydro-2H-pyran-2-
yl)oxy)propoxy)carbonyl)oxy)ethyl (2S)-2-
(2-(benzofuran-6-carbony1)-5,7-dichloro-1,2,3,4-tetrahy droi s oquinoline-6-
carb oxami d o)-3 -(3 -
(methyl sulfonyl)phenyl)propanoate. The title compound was afforded as a
yellow oil (101 mg,
52%). LCMS (Method G): Rt = 1.84 min, [M-FI\TH4] = 848Ø
Chemical Synthesis Example 1-18:
105921 1-(((3-Hydroxypropoxy)carbonyl)oxy)ethyl
(25)-2-(2-(benzofuran-6-carbonyl)-5,7-
dichloro-1,2,3,4-tetrahydroisoquinohne-6-carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoate
ci
0
101 r. 0 CI 40
0 cl
0 .
's 0 0 0 0 's 0 0
o e
0 0 0 0 OOOH
105931 To a stirred solution
of 1-(((3-((tetrahydro-2H-pyran-2-
yl)oxy)propoxy)carbonyl)oxy)ethyl
(25)-2-(2-(b enzofuran-6- carb ony1)-5,7-dichloro-1,2,3,4-
tetrahydroi soquinoline-6-carb oxamido)-3 -(3 -(methyl
sulfonyl)phenyl)propanoate (114 mg, 0.135
mmol) in 1,4-dioxane (3.0 mL) at r.t. was added 4M HC1-dioxane (1.0 mL, 4.00
mmol) and the
reaction mixture stirred at r.t. for 18 h. The solvent was evaporated in vacuo
and the crude product
purified by preparative reversed-phase HPLC. Desired fractions were combined,
the solution
-140-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
frozen (-78 C) and the solvent evaporated in vacua (lyophilization) to yield
the title compound
as a white solid (4.9 mg, 5%). LCMS (Method F): Rt = 4.47 min, [M-F1-1] =
761.6.
Chemical Synthesis Example 1-19:
105941 1-(((2-Hydroxyethoxy)carboilyl)oxy)ethyl
(2S)-2-(2-(benzofurarn-6-carbonyl)-5, 7-
dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(inethylsulfanyl)phenyl)propanoate
O
CI 0
N
0 CI
;S.. 0 0 0
0/
0 0
105951 The title compound was synthesized via an analogous method to that
described in
Chemical Synthesis Example 1-18. The title compound was afforded as a white
solid (26.5 mg,
29%). LCMS (Method F): Rt = 4.40 min, [M-FE-I]+ = 747Ø
Chemical Synthesis Example 1-20:
105961 S-(((R)-34(R)-2-Acetamido-2-carboxyethyl)disulfaney1)-8-WS)-2-(2-
(benzofuran-6-
carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsitlfonyOphenyOpropanoyDoxy)methoxi)-8-oxooctyl)thio)-N-acetyl-L-
cysteine
CI
N 0/
11101 _
0 CI CI 0
O N =
/
40 0 0,
0,
-;,s, 0 0
,
0 0 H
SSOH
CI
HNy,
N 0/
_
0
0 CI
0
0- OH
;S 0 0 0
0' 1
105971 To a solution
of 1-4(S)-2-(2-(benzofuran-6-carbony1)-5,7-dichloro-1,2,3,4-
tetrahydroi soquinoline-6-carb oxami do)-3 -(3 -(methyl
sulfonyl)phenyl)propanoyl)oxy)ethyl 5-
((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and
1-(((S)-2-(2-(benzofuran-6-carbony1)-5,7-
dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5-((3R)-1-oxido-1,2-dithiolan-3-
yl)pentanoate (40
-141-
CA 03196146 2023- 4- 18
WO 2022/084739 PCT/IB2021/000708
mg, 0.0463 mmol) in acetone (2.0 mL) was added N-acetyl-L-cysteine (60 mg,
0.370 mmol) and
the reaction mixture stirred at 40 C for 16 days. N-acetyl-L-cysteine (30.2
mg, 0.185 mmol) was
added, and the mixture stirred at 40 C for 9 days. The reaction mixture was
evaporated in vacuo
and the crude product purified by preparative reversed-phase HPLC. Desired
fractions were
combined and the solution frozen (-78 C). The solvent was evaporated in vacuo
(lyophilization)
to yield the title compound as a white solid (3.6 mg, 6.6%). LCMS (Method G):
Rt = 1.77 min,
[M+H] = 1172.8.
Chemical Synthesis Example 1-21:
105981 Step 1; tert-Butyl (1-chloroethyl) succinate
0 0
HOyO
CI
0 0
105991 A mixture of 4-(tert-Butoxy)-4-oxobutanoic acid (300 mg, 1.72 mmol), 1-
chloroethyl
sulfochloridate (0.26 mL, 2.41 mmol), sodium bicarbonate (579 mg, 6.89 mmol)
and tetrabutylammonium hydrogen sulfate (59 mg, 0.172 mmol) were dissolved in
1:1 DCM-H20
(20 mL) and the mixture stirred vigorously at r.t. for 18 h. The reaction
mixture was passed through
a phase separator and the filtrate evaporated in vacuo. The crude product was
purified by flash
chromatography (Biotage Si-SFAR; 25 g) eluting with isohexane ¨> 20% Et0Ac-
isohexane to
yield the title compound as a colorless oil (250 mg, 61%). 1-1-1-NMR (400 MHz,
CDC13) 6 6.53 (q,
J= 5.8 Hz, 1H), 2.44-2.69 (m, 4H), 1.77 (d, J= 5.5 Hz, 3H), 1.43 (s, 9H).
106001 Step 2: 1-(((S)-2-(2-(Benzofuran-6-carbonyl)-
5,7-dichloro-1,2,3,4-
tetrahydroisoquinoline-6-carboxamido)-3-(3-
(niethylsulfonyl)phenyl)propanoyl)oxy)ethyl tert-
butyl succinate
0 ci
0
CI 0
_________________________________________________ J.- 101 0 CI
1101 i 0 CI
'S 0 OH e
e
106011 A mixture of Lifitegrast (100 mg, 0.162 mmol) and tert-butyl (1-
chloroethyl) succinate
(44 mg, 0.185 mmol) were dissolved in DMF (2.0 mL). DIPEA (0.054 mL, 0.310
mmol) was
added, and the mixture stirred at 50 C under N7 for 16 h. The reaction
mixture was purified by
preparative reversed-phase HPLC. Desired fractions were combined and the
solution frozen (-78
-142-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
C), the solvent was evaporated in vacuo (lyophilization) to yield the title
compound as an off-
white solid (34.2 mg, 27%). LCMS (Method F): Rt = 5.28 min, [M-FIN-a] =
837Ø
Chemical Synthesis Example 1-22:
106021 4-(1-(aS)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinohne-6-
carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethoxy)-4-oxobutanoic
acid
ci
0
0 CI 0 CI
O. 0.
;S.., 0 0 0 ;S.., 0 0 0
0 0
106031 To a solution of 1-(((S)-2-(2-(b en zofuran-6-c arb
onyl )-5,7-di chloro-1,2,3,4-
tetrahy droi soquinoline-6-carb oxami do)-3 -(3 -(methyl sulfonyl)phenyl)prop
anoyl)oxy)ethyl tert-
butyl succinate (126 mg, 0.154 mmol) in DCM (1.0 mL) at r.t. was added 20% TFA-
DCM (1.0
mL) and the reaction mixture stirred at r.t. for 8 days. The solvent was
evaporated in vacuo and
the crude product purified by preparative reversed-phase HPLC. Desired
fractions were combined
and the solution frozen (-78 C), the solvent was evaporated in vacuo
(lyophilization) to yield the
title compound as a white solid (68.6 mg, 58%). LCMS QC (Method F): Rt = 4.45
min, [M+H] =
759Ø
Chemical Synthesis Example 1-23:
106041 Step 1: 2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl 5-((S)-1,2-dithiolan-3-
Apentanoate
0
OH
106051 To a solution of lipoic acid (300 mg, 1.42 mmol) and 2-(tetrahydro-2H-
pyran-2-
yloxy)ethanol (208 mg, 1.42 mmol) in DCM (10 mL) at r.t. was added DMAP (35
mg, 0.285
mmol) followed by DCC (294 mg, 1.42 mmol) and the reaction mixture stirred at
r.t. for 18 h. The
solution was washed with water (10 mL), passed through a phase separator and
the filtrate
evaporated in vacuo. The crude product was purified by flash chromatography
(Biotage Si-SFAR;
25 g) eluting with 20% Et0Ac-isohexane ¨> 50% Et0Ac-isohexane to yield the
title compound
as a yellow oil (278mg, 58%). LCMS (Method G): Rt = 1.98 min, 1M-THP-411 =
251.1.
-143-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
106061 Step 2: 2-Hydroxyethyl (R)-5-(1,2-dithiolan-3-yOpentanoate
0 0
S,
106071 To a solution of 2-tetrahydropyran-2-yloxyethyl 5-1(3R)-dithiolan-3-
yl]pentanoate (278
mg, 0.831 mmol) in DCM (10 mL) was added 20% TFA-DCM (10 mL) and the reaction
mixture
stirred at r.t. for 3 h. The solvent was evaporated in vacuo and the residue
partitioned between
DCM (15 mL) and sat. NaHC0300 (15 mL). The organic phase was passed through a
phase
separator and the filtrate evaporated in vacno to yield the title compound as
an orange oil (170 mg,
82%). The material was used in the next step without further purification.
106081 Step 3: 2-(0-Chloroethoxy)carbonyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-
yOpentanoate
0 0
0
106091 To a solution of 2-hydroxyethyl (R)-5-(1,2-dithiolan-3-yl)pentanoate
(170 mg, 0.679
mmol) in DCM (10 mL) at r.t. was added pyridine (110 1.1.L, 1.37 mmol)
followed by 1-
chloroethyl chloroformate (73 [IL, 0.679 mmol) and the reaction mixture
stirred at r.t. for 16 h.
The solution was washed with water (15 mL), passed through a phase separator
and the filtrate
evaporated in men . The crude product was purified by flash chromatography
(Biotage Si-SFAR;
25 g) eluting with DCM ¨> 20% Et0Ac-DCM to yield the title compound as a
colorless oil (41.2
mg, 17%). The material was used in the next step without further purification.
106101 Step 4: (3S)-1-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-
tetrahydroisoquitiolin-6-
y1)-6-methyl-3-(3-(methylsulfonyl)benzy1)-1,4,8-trioxo-5,7,9-trioxa-2-
azaundecati-11-y1 5-((R)-
1,2-dithiolart-3-yl)pentanoate
CI
CI 0H
0,
0 CI
401 0 CI
S,... 0 0 0
s-S
0 OH 0' k
0
106111 To a solution of 2-(((1-chloroethoxy)carbonyl)oxy)ethyl 5-((R)-1,2-
dithiolan-3-
yl)pentanoate (41 mg, 0.115 mmol) in DMF (1.0 mL) was added Lifitegrast (75
mg, 0.122 mmol)
and D1PEA (50 L, 0.287 mmol) and the reaction mixture stirred at 50 C in a
sealed vial for 40
h. The crude product was purified by preparative reversed-phase HPLC. Desired
fractions were
-144-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
combined and the solution frozen (-78 C). The solvent was evaporated in vacuo
(lyophilization)
to yield the title compound as an orange solid (13.2 mg, 12%). LCMS (Method
F): Rt = 5.51 min;
[M+H]+ = 935Ø
Chemical Synthesis Example 1-24:
[0612] Step 1: 3-((letrahydro-21-1-pyran-2-y1)oxy)propyl 5-((R)-1,2-dithiolan-
3-yl)pentanoate
0
0 0 0)-C3
[0613] 3 -((T etrahy dro-2H-pyran-2 -yl)oxy)propyl 5-((R)-1,2-dithi ol an-3
-yl)p entanoate was
synthesized via an analogous method to the method described in step 1 in
Chemical Synthesis
Example 1-23. 3 -((T etrahy dro-2H-pyran-2-yl)oxy)propyl 5-((R)-1,2-dithi olan-
3-yl)pentanoate
was afforded as a yellow oil (232 mg, 47%). LCMS (Method G): Rt = 2.04 min, [M-
THP+H] =
265.1.
[0614] Step 2: 3-Hydroxypropyl (R)-5-(1,2-dithiolan-3-yl)pentanoate
0
H S=s
[0615] 3-Hydroxypropyl (R)-5-(1,2-dithiolan-3-yl)pentanoate was synthesized
via an analogous
method to the method described in step 2 in Chemical Synthesis Example 1-23. 3-
Hydroxypropyl (R)-5-(1,2-dithiolan-3-yl)pentanoate was afforded as an orange
oil (346 mg crude
material), and was used in the next step without further purification.
[0616] Step 3: 3-(0-Chloroethoxy)carbonypoxy)propyl 5-((R)-1,2-dithiolan-3-
yl)pentanoate
9 0
CI- 0 0
[0617] 3 -(((l-Chl oroethoxy)carb onyl)oxy)propyl 5-((R)-1,2- dithi ol an-3
-yl)p entanoate was
synthesized via an analogous method to the method described in step 3 in
Chemical Synthesis
Example 1-23. 3-4(1-Chl oroethoxy)carbonyl)oxy)propyl 5-((R)-1,2-dithi ol an-3
-yl )pentan oate
was afforded as a yellow oil (164 mg, 66%), and was used in the next step
without further
purification.
[0618] Step 4: (3S)-1-(2-(Benzofuran-6-carbony1)-5,7-dichloro-1,2,3,4-
tetrahydroisoquinolin-6-
y1)-6-methy1-3-(3-(methylsulfonyl)benzyl)-1,4,8-trioxo-5,7,9-trioxa-2-
azadodecan-12-y1
dithiolan-3-yl)pentanoate
-145-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
O
CI 0
E 0 CI
0,
0 0 0 0
0'
S\
[0619] The title compound was synthesized via an analogous method to the
method described in
step 4 in Chemical Synthesis Example 1-23. The title compound was afforded as
a white solid
(7.7 mg, 1.8%). LCMS (Method F): Rt = 5.61 min, [M+H] = 949.1.
106201 The rest of the compounds provided herein (e.g., in Table 1 or Table 2)
are prepared
according to a similar process as provided for any of the Chemical Synthesis
Examples, such as,
for example, Chemical Synthesis Example 1 hereinabove, such as, for example,
starting from
lifitegrast.
II. Biological Evaluation
Example II-1: Rabbit Cornea Homogenate Stability Assay
106211 Determining Rabbit Cornea Homogenate stability of the test compounds
was performed
using HPLC-MS or UPLC-MS. The assay was performed at two concentrations of
Rabbit Cornea
Homogenate (0.15 mg/mL and 0.45 mg/mL total protein) so that any hydrolysis
observed can be
assigned as esterase dependent or not.
Rabbit Cornea Homogenisation
[0622] Three to five rabbit corneas (e.g. New Zealand Whites (NZW) or Dutch
Belted (DB)) of
approx. 50 mg each were sliced and scraped with a scalpel and tweezers until
reduced to small (1-
3 mm), thin pieces. These were transferred into a glass vial containing
approximately 2 mL of
cold DPBS pH 7.4 buffer.
106231 Sample was cooled intermittently on ice and shear homogenized for 3
minutes, then
centrifuged for 3 min at 13,000 g. The supernatant was pipetted off into a
vial, and total protein
concentration determined at 280nm. Sample was stored at -78 C.
Rabbit Cornea Esterase Assay
Method 1
Preparation of stock solutions:
[0624] 10 mM Compound stocks were diluted to 100 ttM in a 96 deep-well plate:
10 !IL of 10
mM Compound stock was added to 990 pi 50 mM HEPES, pH 7.5 buffer. Compounds
were
-146-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
further diluted to 10 04: 100 pL of 100 p,M compound was added to 900 pL 50 mM
HEPES, pH
7.5 buffer. Esterase homogenate was diluted to 300 ng/pL and 900 ng/p.L.
Assay Conditions:
[0625] A heater shaker was set to 37 C. Into a suitable 96 well plate (Run
Plate), 75 p.L of 300 or
900 ng/pL esterase homogenate was pipetted into each of the required wells
(2min, 5min, 10min,
20min and 45 min). The plate was sealed and then warmed at 37 C for 5 min.
[0626] Another 96 well PCR plate was put on ice (Kill Plate). To this was
added 100 [IL of MeCN
to each well, labelled Omin 2min, 5min, 10min, 20min and 45 min The plate was
covered to
minimize evaporation.
[0627] For the T=0 sample only, to the 100 pL cold MeCN stop solution was
added 50 [IL of 300
or 900 ng/pt esterase homogenate followed by 50 [EL of 10 ILIM compound
solution For the
remaining timepoints, 75 pL of 10 p..M compound solution was added to the Run
Plate starting
from T=45 min row and ending with T=2 min row. At the appropriate time point,
100 pL of the
assay mixture was added to the matching kill plate well containing 100 p.L of
cold MeCN. Samples
were analyzed as soon as practicable by LCMS (Waters Xevo TQ-S or Micromass
Ultima).
[0628] Parent conjugate and parent concentrations were determined against
appropriate standard
response curves and the half-life (T1/2) of the parent conjugate was
calculated using the peak area
of the parent conjugate at each time point in the linear region of the log ¨
linear plot.
Method 2
Preparation of stock solutions:
[0629] 10 mM Compound DMSO stocks were diluted to 10 tiM in a glass vial: 10
tiL of 10 mM
Compound stock was added to 9,990 pL DPB S, pH 7.4 buffer. Esterase homogenate
was diluted
to 300 ng/p.L and 900 ng/p.L in DPB S.
Assay Conditions:
[0630] A heater shaker was set to 37 C. Into a suitable 96 well plate (Run
Plate), 70 pL of 300
or 900 ng/pL esterase homogenate was pipetted into two rows as compounds were
analysed in
duplicate (Omin, 2min, 5min, 10min, 20min and 45 min). The plate as sealed and
then warmed at
37 C for 5 min.
[0631] Two 96 deep-well plates were put on ice (Kill Plates). To these, 990 pL
of 50:50 MeCN-
WO were added to required rows, labelled Omin 2min, 5min, 10min, 20min and 45
min. The
plates were covered to minimise evaporation.
-147-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
[0632] To both rows of the Run Plate, 70 uL of 10 uM compound solution was
added. At the
appropriate time point, 10 uL of the assay mixture was added to the matching
kill plate well
containing 990 g.1_, of 50:50 cold MeCN-H20. Samples were analysed as soon as
practicable by
LCMS (Waters Xevo TQ-S).
Assay conditions for lipoic acid analysis:
[0633] A heater shaker was set to 37 C. Into a suitable 96 well plate (Run
Plate), 80 u.1_, of 300
or 900 ng/uL esterase homogenate was pipetted into two rows as compounds were
analyzed in
duplicate (0 min, 2min, 5min, 10min, 20min and 45 min). The plate was sealed
and then warmed
at 37 C for 5 min.
[0634] Two 96 shallow-well plates were placed on ice (Kill Plates). To these,
180 L of 60:40
MeCN-H20 + 0.1% acetic acid were added to required rows. The plates were
sealed to minimise
evaporation.
[0635] To both rows of the Run Plate, 80 uL of 10 uM compound solution was
added. At the
appropriate time point, 20 uL of the assay mixture was added to the matching
kill plate well
containing 180 L of 60:40 cold MeCN-H20 + 0.1% acetic acid. For lipoic acid
analysis, samples
were analysed as soon as practicable by LCMS (Waters Xevo TQ-S). For parent
conjugate and
parent analysis the samples were diluted further 1 in 10: 20 uL supernatant
was added to 180 pi.
of 50:50 MeCN-H20.
[0636] Parent conjugate, parent and keratolytic concentrations were determined
against
appropriate standard response curves and the half-life (T1/2) of the parent
conjugate was
calculated using the peak area or the measured concentration of the parent
conjugate at each time
point in the linear region of the log ¨ linear plot.
Table 3
Esterase %
Cornea Esterase % API
keratolytic
Homogenate Lifitegrast Formation
Comp agent
Method
Conc formation at rate
formation at
(mg/mL) 45 min 45 min ( /0/min)
0.15
2
31
0.45
2
0.15 A A a 1
-148-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0.45 A A a 1
0.15 A - a 2
29
0.45 A - a 2
0.15 A a 2
0.45 A a 2
0.15 C c 2
7 + 9B
0.45 D D d 2
0.15 A - a 2
26
0.45 A - a 2
0.15 A - a 2
32
0.45 B - b 2
0.15 B - b 2
33
0.45 B - c 2
0.15 A a 2
34
0.45 A - a 2
0.15 A - a 2
0.45 A a 2
0.15 A - a 2
36
0.45 B - b 2
0.15 C c 2
37
0.45 D - c 2
38&
0.15 D - d 2
39
-149-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
0.45 D - d 2
0.15 B - b 2
40 &
41
0.45 B - b 2
0.15 B - b 2
43
0.45 C - c 2
0.15 C d 2
42
0.45 C d 2
0.15 A a 2
44
0.45 A - a 2
0.15 A a 2
47
0.45 A - a 2
0.15 A a 2
46
0.45 A a 2
0.15 C c 2
0.45 C - c 2
0.15 B b 2
48
0.45 C - c 2
0.15 A - a 2
0.45 A a 2
0.15 A - a 2
49
0.45 A - a 2
A: percent active pharmaceutical ingredient (API) formation <25%; B: percent
API formation
25% to 50%; C: percent API formation 51% to 75%; D: percent API formation
>75%.
-150-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
a: API formation rate <0.5%/min ; b: API formation rate 0.5-1.0%/min; c: API
formation rate 1.0-
1.5%/min; d: API formation rate >1.5%/min.
Example 11-2: Aqueous hydrolysis stability assay
106371 Determination of aqueous stability of the test compounds was performed
using HPLC-MS
or UPLC-MS. A test compound 10 mM stock solution was prepared in DMSO.half-
life (Tin ) of
the parent conjugate is calculated using the peak area of the parent conjugate
at each time point in
the linear region of the log ¨ linear plot.
Method 1
106381 10 tiL of the DMSO stock solution was dissolved in 990 tiL of 50 mM
HEPES pH 7.5
buffer or 1:1 (v/v) of acetonitrile:water to make a 100 uM solution. Final
DMSO concentration
was 1%. The solution was kept at room temperature and injected without delay
into the LCMS
(Waters Xevo TQ-S or Micromass Ultima). Additional injections were performed
at appropriate
time points.
Method 2
uL of the DMSO stock solution is dissolved in 990 [11_, of DPBS pH 7.4 buffer
to prepare 100
uM solution. A further dilution is made by dissolving 75 uL of 100 uM stock
solution into 225
uL of DPBS. Final DMSO concentration is 0.25%. The solution is kept at 37 C
and injected
without delay into the LCMS (Waters Xevo XSQ-ToF). Additional injections are
performed at
appropriate time points.
Table 4
Hydrolytic % Lifitegrast
Comp Method
formation at [time]
31 C [60 min] 2
5 C [45 min] 1
7 + 9B A [45 min] 2
45 C [44 min] 2
A. percent active pharmaceutical ingredient (API) formation <1.5%, B. percent
API formation
1.5-4%; C: percent API formation >4%.
-151-
CA 03196146 2023- 4- 18
WO 2022/084739
PCT/IB2021/000708
Example 3: Mouse Model of Experimental Dry Eye Disease
106391 Female C57BL/6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8
weeks old) are
commercially obtained. Experimental dry eye is induced as described by
Niederkom, et al. (J.
Immunol. 2006,176:3950-3957) and Dursun et al. (Invest. Ophthalmol. Vis. Sci.
2002, 43:632-
638). In brief, mice are exposed to desiccating stress in perforated cages
with constant airflow
from fans positioned on both sides and room humidity maintained at 30% to 35%.
Injection of
scopolamine hydrobromide (0.5 mg/0.2 mL; Sigma-Aldrich, St. Louis, MO) is
administered
subcutaneously, three times a day (8:00 AM, 12:00 noon, and 5:00 PM), on
alternating hind-flanks
to augment disease. Mice are exposed to desiccating stress for 3 weeks.
Untreated control mice
are maintained in a nonstressed environment at 50% to 75% relative humidity
without exposure
to forced air. Test animals are exposed to test compound and subsequently tear
samples are
obtained to determine stability of test compounds, and tissue samples are
taken to determine
presence of pro-inflammatory biomarkers.
III. Preparation of Pharmaceutical Dosage Forms
Example III-I: Solution for topical ophthalmic use
106401 The active ingredient is a compound of Table 1, Table 2, a stereoisomer
thereof, or a
pharmaceutically acceptable salt thereof, and is formulated as a solution with
a concentration of
from 0.1-1.5% w/v.
-152-
CA 03196146 2023- 4- 18
